Amide substituted imidazo compounds as selective inhibitors of indoleamine 2, 3-dioxygenase

文档序号：491659 发布日期：2022-01-04 浏览：22次中文

阅读说明：本技术 作为吲哚胺2,3-双加氧酶的选择性抑制剂的酰胺取代的咪唑并化合物 (Amide substituted imidazo compounds as selective inhibitors of indoleamine 2, 3-dioxygenase ) 是由王鹤翔邱明周昌友于 2020-05-21 设计创作，主要内容包括：本文披露了酰胺取代的咪唑并化合物和包含至少一种此类新颖的苯并咪唑的药物组合物、其制备方法以及将其用于疗法中的方法。特别地,本文披露了某些酰胺取代的咪唑并化合物,这些化合物可用于抑制吲哚胺2,3-双加氧酶并治疗由此介导的疾病或障碍。(Amide substituted imidazo compounds and pharmaceutical compositions comprising at least one such novel benzimidazole, methods of their preparation, and methods of their use in therapy are disclosed. In particular, certain amide substituted imidazo compounds are disclosed that are useful for inhibiting indoleamine 2, 3-dioxygenase and for treating diseases or disorders mediated thereby.)

1. A compound having the formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

m is CH or N;

w is CH or N;

p is 1,2 or 3;

q is 0, 1 or 2;

x is-CR⁵R⁶-、-CHR⁵CHR⁶-or a single bond;

R⁵and R⁶Each independently of the others is hydrogen, halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6A cycloalkyl group; or (R)⁵And R⁶) And/or (R)⁵And Y) together with one or more of the atoms to which they are attached form a fused C_3-8A cycloalkyl ring, and said ring being optionally substituted by halogen, C_1-4Haloalkyl and C_1-4Alkyl substitution;

y and Z are each independently selected from hydrogen, halogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl; or Z and Y together with one or more atoms to which they are attached form a bridging ring or heterocyclic ring, which is optionally substituted with a substituent selected from: halogen, C_1-4Haloalkyl, C_1-4Alkyl and C_1-4An alkoxy group;

ring a is a monocyclic aromatic hydrocarbon ring or a bicyclic aromatic hydrocarbon ring, or a monocyclic aromatic heterocycle or a bicyclic aromatic heterocycle, each of which has 5 to 10 ring members; and ring A is optionally substituted, as far as valency and stability permit, by at least one substituent R⁷Substitution;

E₁、E₂、E₃and E₄Each independently selected from CR³Or N;

R³each independently selected from hydrogen, halogen, cyano, C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) NR¹R²Nitro, -C (O) OR¹、-C(O)R¹、-OR¹、-SR¹、-NR¹R²、-SO₂R¹、-SO₂NR¹R²、-SOR¹、-NR¹SO₂R²、-NR¹SOR²、-NR¹C(O)OR²or-NR¹C(O)R²Wherein said C is_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, C_3-8Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with 1 or 2 substituents R¹⁰Substitution;

R¹and R²Each independently is H, C_1-8Alkyl radical, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C_1-8Alkyl radical, C_3-8Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted1 or 2 substituents R¹⁰Substituted, or R¹And R²Together with the nitrogen atom to which they are attached form a ring comprising 0, 1,2,3 or 4 additional heteroatoms selected from-NH, -O-, -S-, -SO-or-SO₂-, and said ring is optionally substituted by at least one substituent R¹⁰Substitution;

with the proviso that₁、E₂、E₃And E₄Is at least one of CR³Wherein R is³is-C (O) NR¹R²Wherein R is¹And R²As defined above;

alternatively, two adjacent R³If present, together with the atom or atoms to which they are attached form a lactam ring, said ring containing, in addition to the nitrogen atom forming the lactam ring, 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or sulfur, and said ring being optionally substituted by halogen, C_1-4Haloalkyl and C_1-4Alkyl substitution;

R⁷independently selected from hydrogen, halogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, C_3-8Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with 1 or 2 substituents R¹⁰Substitution;

R¹⁰independently at each occurrence is hydrogen, halogen, C_1-8Haloalkyl, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, -C_1-4alkyl-NR^aR^b、-CN、-OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-CONR^aR^b、-C(＝NR^a)NR^bR^cNitro, -NR^aC(O)R^b、-NR^aC(O)NR^aR^b、-NR^aC(O)OR^b、-SO₂R^a、-NR^aSO₂NR^bR^c、-NR^aSOR^bor-NR^aSO₂R^bWherein said C is_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8The cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are each independently optionally substituted with one, two, or three substituents selected from halo, hydroxy, C_1-4Alkyl radical, C_1-4Alkyloxy, C_1-4Haloalkyl, and C_1-4Haloalkyloxy, wherein R^a、R^bAnd R^cEach independently selected from H, C_1-4Haloalkyl, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with one or more halogen, C_1-4Haloalkyl and C_1-4Alkyl substituted, or (R)^aAnd R^b) And/or (R)^bAnd R^c) Together with one or more atoms to which they are attached form a ring selected from a heterocyclyl or heteroaryl ring optionally substituted with halogen, C_1-4Haloalkyl or C_1-4Alkyl substitution.

2. The compound of claim 1, wherein E₁、E₂、E₃And E₄As defined below:

(a)E₁is CR³，E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is CR³；

(b)E₁Is CR³，E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is CR³；

(c)E₁Is N, E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is CR³；

(d)E₁Is N, E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is CR³；

(e)E₁Is CR³，E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is N;

(f)E₁is CR³，E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is N;

(g)E₁is N, E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is N;

(h)E₁is N, E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is N;

(i)E₁is CR³，E₂is-CC (O) NR¹R²，E₃Is N, and E₄Is CR³；

(j)E₁Is CR³，E₂Is N, E₃is-CC (O) NR¹R²And E is₄Is CR³；

(k)E₁Is N, E₂is-CC (O) NR¹R²，E₃Is N, and E₄Is CR³；

(l)E₁Is CR³，E₂Is N, E₃is-CC (O) NR¹R²And E is₄Is N;

wherein R is¹、R²And R³As defined for formula (I).

3. The compound of claim 1 or 2, wherein p is 1 and q is 1.

4. The compound of claim 1 or 2, wherein p is 1 and q is 0.

5. The compound of claim 1 or 2, wherein W is N and M is CH, or W and M are both N, or W and M are both CH, or W is CH and M is N.

6. A compound as claimed in claim 1 or 2, wherein the compound isIs partially Wherein indicates a connection to ring a, and indicates a connection to X.

7. The compound of claim 1 or 2, wherein X is-CR⁵R⁶-, wherein R⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6Cycloalkyl radical, and R⁶Is hydrogen.

8. The compound of claim 1 or 2, wherein X is-CR⁵R⁶-, wherein R⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6Cycloalkyl radical, and R⁶Is hydrogen, and theIs partiallyWherein indicates a connection to ring a, and indicates a connection to X.

9. The compound of claim 2, wherein the compound of formula (I) is a compound of formula (Ia):

wherein the variable R¹、R²、R⁵、Z、Y、E₁、E₃、E₄And a is as defined for formula (I).

10. The compound of claim 1 or 2, wherein Z and Y, together with the atoms to which they are attached, form a bridged bicyclic ring optionally substituted with a substituent selected from: halogen, C_1-4Haloalkyl, C_1-4Alkyl and C_1-4An alkoxy group; preferably, Z and Y together with the atoms to which they are attached form a bridged bicyclic ring selected from the group consisting of bicyclo [2.2.1]Heptyl (e.g. bicyclo [2.2.1 ]]Hept-2-yl), bornyl-2-yl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.1]Nonyl, or bicyclo [3.3.2.]A decyl group; more preferably, the bridged bicyclic ring is bicyclo [2.2.1]Heptyl or bicyclo [2.2.2]And (4) octyl.

11. The compound of any one of claims 1 or 2 or 9, wherein the compound is selected from formula (Ib):

wherein R is⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6A cycloalkyl group; r⁷Is halogen, R¹、R²、E₁、E₃And E₄As defined for formula (I).

12. The compound of any one of claims 1 or 2 or 9, wherein the compound is selected from one of the following configurations:

wherein R is⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6A cycloalkyl group; r⁷Is halogen, R¹、R²、E₁、E₃And E₄As defined for formula (I).

13. The compound of any one of claims 1 or 2 or 9-12, wherein R¹And R²Each independently is H, C_1-8Alkyl radical, C_3-8Cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein said C is_1-8Alkyl radical, C_3-8Cycloalkyl, or aryl each independently optionally substituted with 1 or 2 substituents R¹⁰Substituted, or R¹And R²Together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, or 6-membered saturated ring containing 0 additional heteroatoms, and which is optionally substituted with at least one substituent R¹⁰And (4) substitution.

14. The compound of claim 13, wherein R¹Is hydrogen or methyl, R²Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyethyl, hydroxycyclobutylmethyl, oxetanyl.

15. The compound of any one of claims 1-2 or 11-14, wherein ring a is a phenyl ring or a naphthyl ring; or a monocyclic aromatic heterocycle or a bicyclic aromatic heterocycle having 5 to 10 ring members containing 1,2,3, or 4 heteroatoms selected from O, S, and N.

16. The compound of claim 15, wherein ring a is a monocyclic aromatic heterocycle having 5 to 6 ring members containing 1 or 2 heteroatoms selected from O, S, and N.

17. The compound of claim 15, wherein ring a is a bicyclic aromatic heterocycle having 8 to 10 ring members containing 1 or 2 or 3 heteroatoms selected from O, S, and N.

18. The compound of claim 17, wherein ring a is a benzothiophenyl (e.g., benzo [ b ] thiophen-2-yl, benzo [ b ] thiophen-3-yl, benzo [ b ] thiophen-5-yl, or benzo [ b ] thiophen-6-yl) or a quinolinyl (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl) or a benzodioxolyl (e.g., benzo [ d ] [1,3] dioxol-5-yl).

19. The compound of claim 18, wherein ring a is quinolinyl (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), optionally substituted with halo or C_1-8Haloalkyl substitution.

20. The compound of claim 1, wherein the compound is selected from the group consisting of:

21. a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

22. A method for treating or preventing a hyperproliferative disorder responsive to inhibition of IDO1, comprising administering to a subject in recognized need thereof an amount of a compound of any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, effective to inhibit said IDO 1.

23. The method of claim 22, wherein the hyperproliferative disorder is cancer.

24. The method of claim 23, wherein the hyperproliferative disorder is selected from: melanoma, thyroid cancer, barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, stomach cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, hematological cancer, large intestine colon cancer, histiocytic lymphoma, or lung adenocarcinoma.

25. A method for treating or preventing HIV infection/AIDS, comprising administering to a subject in recognized need thereof a therapeutically effective amount of a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

26. A method for increasing the effectiveness of antiretroviral therapy comprising administering to a subject in recognized need thereof a therapeutically effective amount of a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Technical Field

Amide substituted imidazo compounds and pharmaceutical compositions comprising at least one such compound, methods of making them, and methods of using them in therapy are disclosed. In particular, certain amide substituted imidazo compounds are disclosed that are useful for inhibiting indoleamine 2, 3-dioxygenase and for treating diseases or disorders mediated thereby.

Background

Indoleamine 2, 3-dioxygenase 1(IDO1, EC 1.13.11.42, also known as indoleamine 2, 3-dioxygenase) is the first enzyme in the tryptophan-kynurenine pathway and is the rate-limiting enzyme, which degrades the essential amino acid L-tryptophan (L-Trp) to N-formyl-kynurenine, which can then be metabolized in a series of steps to form NAD. The IDO1 enzyme is expressed in placenta, mucosa and lymphoid tissues as well as inflammatory lesions (Yamazaki F, et al, Biochem J. [ J. Biochem ] 1985; 230: 635-8; Blastchitz A, et al, ploS ONE. [ public science library complex ] 2011; 6: e 21774). In the latter two, the IDO1 enzyme is expressed primarily by Antigen Presenting Cells (APCs), primarily Dendritic Cells (DCs) and macrophages, as well as cells exposed to interferon-gamma (IFN γ) and other proinflammatory stimuli. In human cells, L-Trp depletion due to IDO1 activity and the production of a series of immunoregulatory metabolites (collectively referred to as "kynurenines") can inhibit proliferation and differentiation of effector T cells [ Frumento G, et al, (2002), Journal of Experimental Medicine [ J.eImmaturing Med ]196:459-468], and significantly enhance the inhibitory activity of regulatory T cells [ Sharma MD, et al (2009), Blood [ Blood ]113:6102-6111 ]. Thus, in a variety of situations (including pregnancy [ Munn DH, et al (1998), Science [ Science ]281:1191-, nature Immunology [ natural Immunology ]3:1097-1101 ].

Some evidence suggests that IDO is involved in inducing immune tolerance. The immunosuppressive effect of IDO1 was first demonstrated in a mouse model that protected the fetus from maternal immune rejection. Treatment of pregnant mice with tryptophan analogues that inhibit IDO1, which is constitutively expressed in the placenta, results in T cell-mediated allogeneic embryo rejection [ Munn DH, et al (1998), Science [ Science ]281:1191-1193 ]. Subsequent studies have evolved this concept into a mechanism to defeat immune surveillance in cancer (reviewed in [ Prendergast GC (2008), Oncogene [ Oncogene ]27(28): 3889-. Indoleamine 2, 3-dioxygenase is widely overexpressed in tumor cells, which is mainly associated with poor prognosis [ Uyttenhove C, et al, (2003), Nat Med [ Nature medicine ]9(10): 1269-; liu X, et al, (2009), Curr Cancer Drug Targets [ contemporary Cancer Drug Targets ]9(8): 938-95). IDO expression from immunogenic mouse tumor cells prevents rejection by pre-immunized mice [ Uyttenhove c, et al, Nat Med. [ natural medicine ]10 months 2003; 9(10) 1269-74.2003, 21 months and 9 days electronic publication. Shows that IDO activity inhibits T cells [ Fallarino F, et al, (2002), Cell Death Differ [ Cell Death and differentiation ]9: 1069-1077; frumento G, et al, (2002), J Exp Med [ journal of Experimental medicine ]196(4): 459-468; ternesss P, et al, (2002), JExp Med [ journal of Experimental medicine ]196(4): 447-. It has been suggested that the efficacy of therapeutic vaccination in cancer patients may be improved by the simultaneous administration of IDO inhibitors [ Uyttenhove c, et al, Nat Med. [ natural medicine ]10 months 2003; 9(10) 1269-74.2003, 21 months and 9 days electronic publication. IDO inhibitors (1-MT) have been shown to act synergistically with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition may also enhance the anti-tumor activity of conventional cytotoxic therapies [ Muller AJ, et al, Nat Med. [ natural medicine ] month 3 2005; 11(3):312-9]. It has been shown that IDO inhibitors can synergistically inhibit tumor growth with anti-CTLA-4 or anti-PD L-1 antibodies in a mouse model [ Holmgaard RB, et al, J Exp Med. [ journal of experimental medicine ]2013, month 7, day 1; 210(7) 1389-402; spranger S, et al, J Immunotherer Cancer [ J.Immunotherapy for Cancer ]2014,2: 3.

It has been proposed that IDO is chronically induced by HIV infection and is further increased by opportunistic infections, and that chronic loss of Trp initiates mechanisms leading to cachexia, dementia and diarrhea and possibly immunosuppression in AIDS patients [ Brown, et al, 1991, adv. exp. med.biol. [ experimental medical and biological progress ],294:425-35 ]. For this reason, it has recently been shown that IDO inhibition can increase the levels of virus-specific T cells in HIV mouse models, and at the same time reduce the number of virus-infected macrophages [ Portula et al, 2005, Blood [ Blood ],106:2382-90 ]. Simian Immunodeficiency Virus (SIV) is very similar to Human Immunodeficiency Virus (HIV) and is used to study disorders in animal models. In HIV and SIV, the level of virus (or ' viral load ') in the blood is important because when the viral load is high, the disease progresses and the patient's immune system is depleted. This ultimately leads to the onset of Acquired Immune Deficiency Syndrome (AIDS), where patients are unable to fight infections that are not harmful to healthy individuals. It has also been reported that treatment of monkeys with simian form of HIV with an IDO inhibitor, known as D-1mT, together with antiretroviral therapy (ART), reduces the viral levels in their blood to undetectable levels, and therefore when combined with ART, IDO inhibitors may contribute to future HIV patients who do not respond to treatment [ Adriano Boasso, et al, j.immunol. [ journal of immunology ], 4 months 2009; 182:4313-4320].

In view of experimental data showing the role of IDO in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV infection, AIDS (including manifestations thereof such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis) and depression, therapeutic agents aimed at inhibiting tryptophan degradation by inhibiting IDO activity are of interest. Inhibitors of IDO may be useful as effective cancer therapies because they can reverse the immunosuppressive effects of the tumor microenvironment and activate the anti-tumor activity of T cells. IDO inhibitors may also be useful for activation of immune responses in HIV infection. Inhibition of IDO may also be an important therapeutic strategy for patients with neurological or neuropsychiatric diseases or disorders, such as depression. The compounds, compositions, and methods herein help meet the current need for IDO modulators.

Tryptophan 2, 3-dioxygenase (TDO, EC 1.13.11.11) catalyzes the same degradation reaction of Trp as IDO 1. TDO is expressed primarily in the human liver, where it acts as a major regulator of the systemic tryptophan level. More recently, TDO has also been found to be expressed in the Brain where it can modulate the production of neuroactive tryptophan metabolites (such as kynurenic acid and quinolinic acid) [ Kanai M, et al, Mol Brain 2009; 2:8]. Two recent studies [ optitz CA, et al, Nature [ Nature ] 2011; 478: 197-; pilotte L, et al, Proc Natl Acad Sci U S A [ Proc Natl Acad Sci U.S. ]2012,109(7): 2497-. Functional studies on human tumors indicate that constitutive TDO enzymatic activity is sufficient to maintain biologically relevant tryptophan metabolism capable of inhibiting anti-tumor immune responses [ optiz CA, et al, Nature [ Nature ] 2011; 478: 197-; pilot L, et al, Proc Natl Acad Sci U S A. [ Proc. Natl. Acad. Sci. USA ]2012,109(7): 2497-. Tumor TDO expression has been reported to prevent rejection in immunized mice. Specific TDO inhibitors have been shown to restore mice' S rejection of TDO-expressing tumors without producing significant toxicity [ Pilot L, et al, Proc Natl Acad Sci U S A. [ Proc Natl Acad Sci ]2012,109(7): 2497-. Thus, inhibitors of TDO may be used as single agents or in combination with other anti-cancer therapies to treat various human cancers.

Small molecule inhibitors of IDO are being developed to treat or prevent IDO-related diseases as described above. For example, PCT publication WO 99/29310 reports a method for altering T-cell mediated immunity that involves altering the local extracellular concentrations of tryptophan and tryptophan metabolites using inhibitors of IDO (e.g., 1-methyl-DL-tryptophan, p- (3-benzofuranyl) -DL-alanine, p- [ 3-benzo (b) thienyl ] -DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999). Methods for making antigen presenting cells for enhancing or reducing T cell tolerance are reported in WO 03/087347 (also disclosed as european patent 1501918) (Munn, 2003). Compounds having indoleamine-2, 3-dioxygenase (IDO) inhibitory activity are further reported in: WO 2004/094409; WO 2006/122150; WO 2009/073620; WO 2009/132238; WO 2011/056652, WO 2012/142237; WO 2013/107164; WO 2014/066834; WO 2014/081689; WO 2014/141110; WO 2014/150646; WO 2014/150677; WO 2015006520; WO 2015/067782; WO 2015/070007; WO 2015/082499; WO 2015/119944; WO 2015/121812; WO 2015/140717; WO 2015/150697; WO 2015/173764; WO 2015/188085; WO 2016/026772; WO 2016/024233; WO 2016/026772; WO 2016/037026; WO 2016/040458; WO 2016/051181; WO 2016/059412; WO 2016/071283; WO 2016/071293; WO 2016/073738; WO 2016/073770; WO 2016/073774; US 2015328228; US 2015266857; WO 2016/155545; WO 2016/161279; WO 2016/161279; WO 2016/161269; WO 2016/165613; WO 2016/16942; 1WO 2016/210414; WO 2017/002078; WO 2017/007700; WO 2017/024996; WO 2017/075341; WO 2017/101884; WO 2017/106062; WO 2017/117393; WO 2017/120591; WO 2017/124822; WO 2017/129139; WO 2017/133258; WO 2017/134555; WO 2017/139414; WO 2017/140272; WO 2017/140274; WO 2017/143874; WO 2017/149469; WO 2017/152857; WO 2017/153459; WO 2017/181849; WO 2017/185959; WO 2017/189386; WO 2017/192811; WO 2017/192815; WO 2017/192813; WO 2017/192840; WO 2017/192844; WO 2017/19514; WO 2018/039512. In particular, WO 2018/039512 discloses benzo [ d ] imidazole, imidazo [1,2-b ] pyridazine, imidazo [1,2-b ] pyridine and some other compounds showing IDO inhibitory activity.

However, there is an unmet need for IDO inhibitors that exhibit potent inhibitory activity against IDO and that exhibit low human plasma protein binding affinity and that can achieve maximum efficacy in humans using lower drug than higher free drug fractions.

Disclosure of Invention

Unexpectedly, the inventors of the present invention found that substitution of the amide group on the imidazo compound confers potent IDO1 inhibitory activity and significantly reduces the human plasma protein binding affinity of the amide-substituted imidazo compound compared to the non-amide compound.

Disclosed herein are compounds having the formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

m is CH or N;

w is CH or N;

p is 1,2 or 3;

q is 0, 1 or 2;

x is-CR⁵R⁶-、-CHR⁵CHR⁶-or a single bond;

E₁、E₂、E₃and E₄Each independently selected from CR³Or N;

R¹and R²Each independently is H, C_1-8Alkyl radical, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C_1-8Alkyl radical, C_3-8Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with 1 or 2 substituents R¹⁰Substituted, or R¹And R²Together with the nitrogen atom to which they are attached form a ring comprising 0, 1,2,3 or 4 additional heteroatoms selected from-NH, -O-, -S-, -SO-or-SO₂-, and said ring is optionally substituted by at least one substituent R¹⁰Substitution;

with the proviso that₁、E₂、E₃And E₄Is at least one of CR³Wherein R is³is-C (O) NR¹R²Wherein R is¹And R²As defined above;

R¹⁰independently at each occurrence is hydrogen, halogen, C_1-8Haloalkyl, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, -C_1-4Alkyl radical-NR^aR^b、-CN、-OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-CONR^aR^b、-C(＝NR^a)NR^bR^cNitro, -NR^aC(O)R^b、-NR^aC(O)NR^aR^b、-NR^aC(O)OR^b、-SO₂R^a、-NR^aSO₂NR^bR^c、-NR^aSOR^bor-NR^aSO₂R^bWherein said C is_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8The cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are each independently optionally substituted with one, two, or three substituents selected from halo, hydroxy, C_1-4Alkyl radical, C_1-4Alkyloxy, C_1-4Haloalkyl, and C_1-4Haloalkyloxy, wherein R^a、R^bAnd R^cEach independently selected from H, C_1-4Haloalkyl, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with one or more halogen, C_1-4Haloalkyl and C_1-4Alkyl substituted, or (R)^aAnd R^b) And/or (R)^bAnd R^c) Together with one or more atoms to which they are attached form a ring selected from a heterocyclyl or heteroaryl ring optionally substituted with halogen, C_1-4Haloalkyl or C_1-4Alkyl substitution.

Also disclosed herein are pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and a compound selected from a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, disclosed herein.

Also disclosed herein are methods of treating cancer responsive to inhibition of IDO and/or TDO, comprising administering to a subject in need of treatment for such cancer an amount of a compound selected from a compound of formula (I) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, effective to treat the cancer.

Also disclosed herein is the use of a compound selected from compounds of formula (I), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as disclosed herein, in the manufacture of a medicament for the treatment of the above disorders or diseases.

Also disclosed herein is the use of a compound selected from the compounds of formula (I) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting IDO and/or TDO.

Also disclosed herein is the use of a compound selected from compounds having formula (I), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as disclosed herein, in the manufacture of a medicament for the treatment of cancer.

Detailed Description

As used herein, the following words, phrases and symbols are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.

The following abbreviations and terms have the indicated meanings throughout:

the phrase "an" entity as used herein refers to one or more of the entities. For example, a compound refers to one or more compounds or at least one compound. As another example, "… substituted with one substituent …" means that one or more substituents are substituted as valency and stability permits. Thus, the terms "a/an", "one or more", and "at least one" are used interchangeably herein.

The term "alkyl" herein refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups containing from 1 to 18 (e.g., from 1 to 12, further e.g., from 1 to 10, still further e.g., from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. Alkyl groups containing from 1 to 6 carbon atoms (i.e. C)_1-6Alkyl) include, but are not limited to: methyl, ethyl, 1-or n-propyl ("n-Pr"), 2-or isopropyl ("i-Pr"), 1-or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropaneA radical or sec-butyl ("s-Bu"), a 1, 1-dimethylethyl or tert-butyl ("t-Bu"), a 1-pentyl radical, a 2-pentyl radical, a 3-pentyl radical, a 2-methyl-2-butyl radical, a 3-methyl-1-butyl radical, a 2-methyl-1-butyl radical, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl groups.

The term "alkyloxy" herein refers to an oxygen-bonded alkyl group as defined above, represented by-O-alkyl. Alkyloxy (e.g. C)_1-6Alkyloxy or C_1-4Alkoxy) include, but are not limited to: methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy and the like.

The term "haloalkyl" herein refers to an alkyl group wherein one or more hydrogens are replaced with one or more halogen atoms (e.g., fluorine, chlorine, bromine, and iodine). Examples of haloalkyl include C_1-6Haloalkyl or C_1-4Haloalkyl, but not limited to F₃C-、ClCH₂-、CF₃CH₂-、CF₃CCl₂-and the like.

The term "alkenyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups comprising at least one C ═ C double bond and from 2 to 18 (e.g. from 2 to 8, further e.g. from 2 to 6) carbon atoms. Alkenyl radicals (e.g. C)_2-6Alkenyl) include, but are not limited to: vinyl (ethenyl or vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1, 3-dienyl groups.

The term "alkynyl" herein refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups containing at least one C ≡ C triple bond and from 2 to 18 (e.g. from 2 to 8, further e.g. 2 to 6) carbon atoms. Alkynyl radicals (e.g. C)_2-6Alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups。

The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups containing monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group may contain from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, a cycloalkyl group may be selected from monocyclic groups comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl radicals (e.g. C)_3-8Cycloalkyl) groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged to be selected from [4,4]、[4,5]、[5,5]、[5,6]And [6,6]]Bicyclic rings of ring systems, or arranged to be selected from bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Bridged bicyclic rings of nonane. Other examples of bicyclic cycloalkyl groups include those arranged to be selected from [5, 6%]And [6,6]]Of two rings of a ring system, e.g. ofWherein the wavy line represents the point of attachment. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated, and is non-aromatic, aromatic as defined herein.

The term "aryl", used alone or in combination with other terms, refers to a group selected from:

5-and 6-membered carbocyclic aromatic rings, such as phenyl;

bicyclic ring systems, such as 7-to 12-membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, for example selected from naphthalene and indane; and

tricyclic ring systems, such as 10-to 15-membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., fluorene.

The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C)_5-10Aryl). Examples of monocyclic aromatic hydrocarbon rings or bicyclic aromatic hydrocarbon rings include, for example, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracenyl, phenanthrenyl rings, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term "halogen" or "halo" as used herein refers to F, Cl, Br or I.

The term "heteroaryl" herein refers to a group selected from:

a 5-to 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from N, O and S, for example from 1 to 4, or in some embodiments from 1 to 3, with the remaining ring atoms being carbon;

an 8-to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O and S, such as from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

an 11-to 14-membered tricyclic ring comprising at least one heteroatom selected from N, O and S, for example from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form an N-oxide.

The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic aromatic heterocycle or bicyclic aromatic heterocycle has 5 to 10 ring members, wherein 1,2,3, or 4 heteroatom ring members are independently selected from nitrogen, sulfur, and oxygen, and the remaining ring members are carbon. In some embodiments, the monocyclic aromatic heterocycle or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the monocyclic aromatic heterocycle or bicyclic aromatic heterocycle is a 5-to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the monocyclic aromatic heterocycle or bicyclic aromatic heterocycle is an 8-to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

Examples of heteroaryl groups, or monocyclic aromatic heterocycles or bicyclic aromatic heterocycles include, but are not limited to: (numbering starting from the attachment position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, or 1,3, 4-thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl), 1,2, 4-oxadiazolyl, or 1,3, 4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2, 3-triazolyl, 1,2, 4-triazolyl, or 1,3, 4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (e.g., 1H-pyrrolo [2,3-b ] pyridin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo [3,4-b ] pyridin-5-yl), benzoxazolyl (e.g., benzo [ d ] oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2, 3-oxadiazolyl, 1-oxa-2, 4-oxadiazolyl, 1-oxa-2, 5-oxadiazolyl, 1-oxa-3, 4-oxadiazolyl, 1-thia-2, 3-oxadiazolyl, 1-thia-2, 4-oxadiazolyl, 1-thia-2, 5-oxadiazolyl, 1-thia-3, 4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolonyl, quinazolinyl, quinoxalinyl, naphthyridinyl, fluoropyridyl, benzothiazolyl (e.g., benzo [ d ] thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7, 8-tetrahydroisoquinoline.

As used herein, the term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a ring selected from 4-to 12-membered monocyclic, bicyclic, and tricyclic saturated and partially unsaturated rings, said ring containing at least one carbon atom in addition to at least one heteroatom selected from oxygen, sulfur, and nitrogen (e.g., from 1-4 heteroatoms, further e.g., from 1-3, or further e.g., 1 or 2 heteroatoms). In some embodiments, the heterocyclyl group is a 4-to 7-membered monocyclic ring having one heteroatom selected from N, O and S. Herein, "heterocycle" also refers to a 5-to 7-membered heterocycle fused to a 5-, 6-and/or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, the 5-to 7-membered heterocycle containing at least one heteroatom selected from N, O and S, with the proviso that when the heterocycle is fused to a carbocyclic aromatic or heteroaromatic ring, the point of attachment is at the heterocycle, and when the heterocycle is fused to a cycloalkyl, the point of attachment may be at the cycloalkyl or heterocycle. "heterocycle" herein also refers to an aliphatic spirocycle comprising at least one heteroatom selected from N, O and S, provided that the point of attachment is at the heterocycle. These rings may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle may be substituted by oxo. The point of attachment may be a carbon or heteroatom in the heterocycle. Heterocycles are not heteroaryl as defined herein.

Examples of heterocycles include, but are not limited to (as numbered from the attachment position designated as priority 1): 1-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thienylpropyl, azetidinyl, oxetanylA group, thietanyl, 1, 2-dithiocyclobutyl, 1, 3-dithiocyclobutyl, dihydropyridyl, tetrahydropyridinyl, thiomorpholinyl, oxathietanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepinyl, oxepinyl, thiepinyl, 1, 4-oxathietanyl, 1, 4-dioxacycloheptyl, 1, 4-oxathietanyl, 1, 4-oxazepinyl, 1, 4-dithiacycloheptyl, 1, 4-thiazepinyl and 1, 4-diazepinyl, 1, 4-dithianyl, 1, 4-azothietanyl, oxazepinylRadical diazaRadical, sulfur nitrogen heteroA group, dihydrothienyl, dihydropyranyl, dihydrofuryl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiocyclopentyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1-dioxo-thiomorpholinyl, 3-azabicyclo [3.1.0 ] group]Hexane radical, 3-azabicyclo [4.1.0 ]]Heptylalkyl, and azabicyclo [2.2.2]A hexyl group. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl.

The term "fused ring" herein refers to a polycyclic ring system, such as a bicyclic or tricyclic ring system, wherein the two rings share only two ring atoms and one common bond. Examples of fused rings may include fused bicycloalkyl rings, such as those having from 7 to 12 ring atoms, arranged as a bicyclic ring selected from the group consisting of the [4,4], [4,5], [5,6] and [6,6] ring systems mentioned above; fused bicyclic aryl rings, such as the 7-to 12-membered bicyclic aryl ring systems mentioned above, fused tricyclic aryl rings, such as the 10-to 15-membered tricyclic aryl ring systems mentioned above; a fused bicyclic heteroaryl ring, such as an 8-to 12-membered bicyclic heteroaryl ring as mentioned above, a fused tricyclic heteroaryl ring, such as an 11-to 14-membered tricyclic heteroaryl ring as mentioned above; and a fused bicyclic or tricyclic heterocyclyl ring as mentioned above.

The compounds disclosed herein may contain asymmetric centers and thus may exist as enantiomers. When the compounds disclosed herein have two or more chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers are intended to be included, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers thereof. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically stated otherwise, reference to one isomer applies to any possible isomer. Whenever the composition of isomers is not specified, all possible isomers are included.

As used herein, the term "substantially pure" means that the stereoisomer of interest contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains no more than 10%, such as no more than 5%, for example no more than 1%, by weight of any one or more other stereoisomers.

When the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers, unless otherwise specified.

Some of the compounds disclosed herein may present different points of attachment of hydrogen, referred to as tautomers. For example, including carbonyl-CH₂Compounds of the c (o) -group (keto form) may undergo tautomerization to form a hydroxy-CH ═ c (oh) -group (enol form). Where applicable, it is also intended to include the individual keto and enol formsAnd mixtures thereof.

It may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired product of each step or series of steps is isolated and/or purified (hereinafter referred to as isolated) to the desired degree of homogeneity by ordinary skill in the art. Typically, such separations involve heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve a number of methods including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated as follows: by reaction with suitable optically active compounds (e.g. chiral auxiliaries, such as chiral alcohols or mosere acid chloride (MosheR)^as acid chloride)) reaction converts a mixture of enantiomers to a mixture of diastereomers, separates the diastereomers, and converts (e.g., hydrolyzes) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

Single stereoisomers (e.g. substantially pure enantiomers) may be obtained by resolution of the racemic mixture using the following method: optically active resolving agents are used to form diastereomers (Eliel, E. and Wilen, S.Stereochemistry of Organic Compounds. [ stereochemistry of Organic Compounds ] New York: John Wiley & Sons, Inc. [ New York: John Wiley & Sons, 1994; Lochmuller, C.H. et al, "Chromatographic resolution of enantiomers: Selective review ]" J.Chromatogr. [ journal of chromatography ]113 (1975): page 283-. The racemic mixture of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) ionic diastereomer salts with chiral compounds and separated by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing reagents, separating the diastereomers and converting to pure stereoisomers; and (3) separating the substantially pure or enriched stereoisomers directly under chiral conditions. See: wainer, Irving w. editors Stereochemistry: Analytical Methods and Pharmacology [ pharmaceutical Stereochemistry: analytical methods and pharmacology ] New York Marcel Dekker, Inc. [ New York: massel deker, 1993.

The term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base group with a suitable organic acid, or separately by reacting the acidic group with a suitable base.

In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is the free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

As defined herein, "pharmaceutically acceptable salts thereof" include at least one salt of a compound having formula (I), and at least one salt of a stereoisomer of a compound having formula (I), e.g., a salt of an enantiomer and/or a salt of a diastereomer.

By "treating" or "ameliorating" is meant administering at least one compound disclosed herein and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof, to a subject in recognized need thereof having, for example, cancer.

The term "effective amount" refers to an amount of at least one compound disclosed herein and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof that is effective to treat a disease or disorder in a subject as defined above.

The term "at least one substituent" as disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents, provided that valency and stability permit. For example, "at least one substituent R" as disclosed herein⁷"comprises from 1 to 4, e.g. from 1 to 3, further such as 1 or 2 substituents selected from R as disclosed herein⁷A list of (a); and "at least one substituent R" as disclosed herein¹⁰"comprises from 1 to 4, e.g. from 1 to 3, further such as 1 or 2 substituents selected from R as disclosed herein¹⁰A list of (a).

In a first aspect, disclosed herein are compounds having formula (I)

Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

m is CH or N;

w is CH or N;

p is 1,2 or 3;

q is 0, 1 or 2;

x is-CR⁵R⁶-、-CHR⁵CHR⁶-or a single bond;

E₁、E₂、E₃and E₄Each independently selected from CR³Or N;

R¹and R²Each independently is H, C_1-8Alkyl radical, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C_1-8Alkyl radical, C_3-8Cycloalkyl, heterocyclyl, arylAnd heteroaryl are each independently optionally substituted by 1 or 2 substituents R¹⁰Substituted, or R¹And R²Together with the nitrogen atom to which they are attached form a ring comprising 0, 1,2,3 or 4 additional heteroatoms selected from-NH, -O-, -S-, -SO-or-SO₂-, and said ring is optionally substituted by at least one substituent R¹⁰Substitution;

with the proviso that₁、E₂、E₃And E₄Is at least one of CR³Wherein R is³is-C (O) NR¹R²Wherein R is¹And R²As defined above;

In one embodiment of the first aspect, p is 1 and q is 1. In another embodiment, p is 1 and q is 0. In one embodiment of the first aspect, W is N and M is CH. In another embodiment, both W and M are N. In yet another embodiment, W and M are both CH. In yet further embodiments, W is CH and M is N.

In one embodiment, Z and Y are each independently selected from hydrogen, halogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, Z and Y, together with the atoms to which they are attached, form a bridged bicyclic ring, optionally substituted with a substituent selected from: halogen, C_1-4Haloalkyl, C_1-4Alkyl and C_1-4An alkoxy group. Preferably, Z and Y together with the atoms to which they are attached form a bridged bicyclic ring selected from the group consisting of bicyclo [2.2.1]Heptyl (e.g. bicyclo [2.2.1 ]]Hept-2-yl), bornyl-2-yl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.1]Nonyl, or bicyclo [3.3.2.]A decyl group. More preferably, the bridged bicyclic ring is bicyclo [2.2.1]Heptyl or bicyclo [2.2.2]And (4) octyl.

Preferably, theIs partially Wherein indicates a connection to ring a, and indicates a connection to X.

In one embodiment, X is-CR⁵R⁶-, wherein R⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6Cycloalkyl radical, and R⁶Is hydrogen.

In another embodiment, X is-CR⁵R⁶-, wherein R⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6Cycloalkyl radical, and R⁶Is hydrogen, and theIs partially Wherein indicates a connection to ring a, and indicates a connection to X. In a further preferred embodiment, R⁵Is methyl, trifluoromethyl, methoxy, or cyclopropyl, and R⁶Is hydrogen. Or (R)⁵And R⁶) And/or (R)⁵And Y) together with the atoms to which they are attached form a fused C_3-8A cycloalkyl ring, and said ring being optionally substituted by halogen, C_1-4Haloalkyl and C_1-4Alkyl is substituted and the ring is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl is preferred.

In some embodiments, ring a is a phenyl ring or a naphthyl ring. In some embodiments, ring a is a monocyclic aromatic heterocycle or a bicyclic aromatic heterocycle having 5 to 10 ring members comprising 1,2,3, or 4 heteroatoms selected from O, S, and N.

In some embodiments, ring a is a monocyclic aromatic heterocycle having 5 to 6 ring members containing 1 or 2 heteroatoms selected from O, S, and N. In other embodiments, ring a is pyridyl, furyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, triazinyl, or pyrazolyl. In some preferred embodiments, ring a is pyridyl or furyl.

In some embodiments, ring a is a bicyclic aromatic heterocycle having 8 to 10 ring members containing 1 or 2 or 3 heteroatoms selected from O, S, and N. In another embodiment, ring a is cinnolinyl, benzothienyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, quinolinyl, isoquinolinyl, pyrrolopyridyl, pyrazolopyridinyl, benzodioxolyl, benzoxazolyl, pteridinyl, purinyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, fluoropyridinyl, benzothiazolyl, or indazolyl. In some preferred embodiments, ring A is a benzothiophenyl group (e.g., benzo [ b ] thiophen-2-yl, benzo [ b ] thiophen-3-yl, benzo [ b ] thiophen-5-yl, or benzo [ b ] thiophen-6-yl) or a quinolinyl group (e.g., quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl) or a benzodioxolyl group (e.g., benzo [ d ] [1,3] dioxol-5-yl).

In one embodiment, ring A isOptionally substituted by one substituent R⁷Substituted, the substituent R⁷Independently of one another is hydrogen, halogen, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-8Haloalkyl, C_3-8Cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In a preferred embodiment, ring A is quinolinyl (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), which quinolinyl is optionally substituted with halogen or C_1-8Haloalkyl substitution. More preferably, ring A is 6-fluoroquinolin-4-yl or 8-fluoro-quinolin-5-yl.

In one embodiment, E₁、E₂、E₃And E₄The combination of (a) and (b) is as follows:

(a)E₁is CR³，E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is CR³；

(b)E₁Is CR³，E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is CR³；

(c)E₁Is N, E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is CR³；

(d)E₁Is N, E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is CR³；

(e)E₁Is CR³，E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is N;

(f)E₁is CR³，E₂Is CR³，E₃is-CC (O) NR¹R²And E is₄Is N;

(g)E₁is N, E₂is-CC (O) NR¹R²，E₃Is CR³And E is₄Is N;

(h)E₁is the sum of the numbers of N,E₂is CR³，E₃is-CC (O) NR¹R²And E is₄Is N;

(i)E₁is CR³，E₂is-CC (O) NR¹R²，E₃Is N, and E₄Is CR³；

(j)E₁Is CR³，E₂Is N, E₃is-CC (O) NR¹R²And E is₄Is CR³；

(k)E₁Is N, E₂is-CC (O) NR¹R²，E₃Is N, and E₄Is CR³；

(l)E₁Is CR³，E₂Is N, E₃is-CC (O) NR¹R²And E is₄Is N;

wherein R is¹、R²And R³As defined for formula (I).

In some embodiments, R³Is halogen, or C_1-8Alkyl (more preferably methyl, ethyl).

In some embodiments, R¹And R²Each independently is H, C_1-8Alkyl (more preferably methyl, ethyl), C_3-8Cycloalkyl (more preferably cyclopropyl, cyclobutyl, cyclohexyl), aryl (e.g. phenyl), heterocyclyl or heteroaryl, wherein said C is_1-8Alkyl radical, C_3-8Cycloalkyl, or aryl each independently optionally substituted with 1 or 2 substituents R¹⁰Substituted, or R¹And R²Together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, or 6-membered saturated ring containing 0 additional heteroatoms, and which is optionally substituted with at least one substituent R¹⁰Substitution; preferably, R¹And R²Together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl).

In some embodiments, R¹Is hydrogen and R²Is C_3-8Cycloalkyl (more preferably cyclopropyl, cyclobutyl, cyclohexyl)) Or aryl (e.g., phenyl), wherein said C_3-8Cycloalkyl, or aryl each independently optionally substituted with 1 or 2 substituents R¹⁰Is substituted in which R¹⁰is-OR^aAnd R is^aIs H, C_1-4Haloalkyl, or C_1-4An alkyl group.

In some embodiments, R¹Is hydrogen and R²Is C_1-8Alkyl radical, wherein said C_1-8Alkyl being optionally substituted by 1 or 2 substituents R¹⁰Is substituted in which R¹⁰Is C_3-8Cycloalkyl or heterocyclyl, said C_3-8The cycloalkyl or heterocyclyl is each independently optionally substituted with one, two or three substituents selected from halo, hydroxy, C_1-4Alkyl radical, C_1-4Alkyloxy, C_1-4Haloalkyl, and C_1-4A haloalkyloxy group.

In one embodiment, R¹And R²Independently selected from hydrogen, C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl-alkyl, aryl, C_1-8Alkyloxy, heterocyclic radical, wherein said C_1-8Alkyl radical, C_3-8Cycloalkyl, aryl each independently optionally substituted with 1 or 2 substituents R¹⁰And (4) substitution. R¹And R¹⁰Independently selected from C_1-8Alkyl radical, C_1-8Alkyloxy, C_3-8Cycloalkyl, wherein said C_1-8Alkyl radical, C_1-8Alkyloxy, C_3-8Cycloalkyl is each independently optionally halogenated, hydroxy, C_1-4Alkyl substitution.

In yet further embodiments, R¹Is hydrogen or methyl, R²Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyethyl, hydroxycyclobutylmethyl, oxetanyl.

In one embodiment, two adjacent R³If present, together with the atom or atoms to which they are attached form a lactam ring, which is

In particular, the compound having formula (I) is a compound having formula (Ia):

wherein the variable R¹、R²、R⁵、Z、Y、E₁、E₃、E₄And a is as defined for formula (I).

In particular, the compound having formula (I) is a compound having formula (Ib):

wherein R is⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6A cycloalkyl group; r⁷Is halogen, R¹、R²、E₁、E₃And E₄As defined for formula (I).

In one embodiment, the compounds disclosed herein have one of the following configurations:

wherein R is⁵Is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, or C_3-6A cycloalkyl group; r⁷Is a halogen. R¹、R²、E₁、E₃And E₄As defined for formula (I).

Also disclosed herein are compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In a fourth aspect, disclosed herein is a process for preparing a compound disclosed herein having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4).

The compounds disclosed herein, and/or pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials along with the disclosure herein.

Compounds having formula (I), including formulae (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), can be prepared by the exemplary methods described in the working examples and the associated published literature procedures used by those skilled in the art. Exemplary reagents and procedures for these reactions appear below and in the working examples. Protection and deprotection in the following methods can be carried out by procedures well known in the art (see, e.g., Greene, T.W. et al, editions by Protecting Groups in Organic Synthesis, 3 rd edition, Wiley [ Willi publishing Co. (1999)). General methods of organic synthesis and functional group transformation are found in the following: trost, B.M. et al, Comprehensive Organic Synthesis, selection, Strategy & Efficiency in model Organic Chemistry [ synthetic Organic Synthesis: selectivity, strategy and efficiency in modern organic chemistry, Pergamon Press [ pegman Press ], new york, state of new york (1991); march, j., Advanced Organic Reactions, mechanics, and Structure [ Advanced Organic Reactions, Mechanisms, and structures ]4 th edition, Wiley & Sons [ john Wiley father, new york, state of new york (1992); katritzky, A.R. et al, edited by Comprehensive Organic Functional Groups Transformations, 1 st edition, Elsevier Science Inc. [ Severe Science, Inc. ], New York, 1995; larock, r.c., Comprehensive Organic Transformations, VCH Publishers, Inc. [ VCH publishing company ], new york, state of new york (1989), and references therein.

The compounds (Ic) of the present invention can be prepared according to the following scheme using chemical transformations familiar to those of ordinary skill in the art of organic/pharmaceutical chemistry. References to many of these transformations can be found in March's advanced Organic Chemistry Reactions, mechanics, and Structure [ March advanced Organic Chemistry: reactions, mechanisms and structures ], 5 th edition, authors Michael b. smith and Jerry March, Wiley-Interscience [ willi international scientific press ], new york, 2001, or other standard texts on the subject of synthetic organic chemistry.

Scheme A

Compound Ic can be prepared by the procedure described in scheme a. The starting acid A-1 is converted to the amide A-3a by coupling with A-2. The amide A-3a may be cyclized to A-4a by treatment with hot acetic acid. The ester A-4a can be hydrolyzed to the acid A-5a by basic conditions. Acid A-5a is converted to the final amide substituted imidazo compound (Ic).

Scheme B

Compound Ia can be prepared by the procedure described in scheme B. The starting acid B-1 is converted into the amide B-3a by coupling with B-2. The amide B-3a may pass through POPh₃And Tf₂The O treatment cyclizes to B-4 a. The ester B-4a can be hydrolyzed to the acid B-5a by alkaline conditions. The acid B-5a is converted to the final amide substituted imidazo compound Ic.

The synthesis of the starting acid and chloride is described in the corresponding examples of the experimental part.

In a fifth aspect, disclosed herein is a method for treating or preventing a hyperproliferative disorder, such as cancer, comprising administering to a subject, such as a mammal or a human, in need thereof a pharmaceutically effective amount of a compound selected from the compounds disclosed herein having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Also disclosed herein are methods for treating or preventing a hyperproliferative disorder, such as cancer, by inhibiting IDO, comprising administering to a subject in need thereof, such as a mammal or human, a pharmaceutically effective amount of a compound selected from the compounds disclosed herein having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Also disclosed herein are methods for treating or preventing cancer, including, for example, melanoma, thyroid cancer, barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, stomach cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, large intestine colon cancer, histiocytic lymphoma, lung adenocarcinoma, the method comprises administering to a subject (such as a mammal or a human) in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as disclosed herein.

Also disclosed herein are methods for treating or preventing HIV/AIDS comprising administering to a subject (such as a mammal or a human) in need thereof a pharmaceutically effective amount of a compound selected from the compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Also disclosed herein are methods for increasing the effectiveness of antiretroviral therapy comprising administering to a subject (such as a mammal or a human) in need thereof an antiretroviral agent and a pharmaceutically effective amount of a compound selected from the group consisting of the compounds disclosed herein having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Also disclosed herein are methods of treating a cancer that is responsive to inhibition of IDO, comprising administering to a subject (such as a mammal or a human) in need of treatment for the cancer a pharmaceutically effective amount of a compound selected from the compounds of formulae (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer includes, but is not limited to, for example, melanoma, thyroid cancer, barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, stomach cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, large intestine colon cancer, histiocytic lymphoma, cancer, Lung adenocarcinoma.

Also disclosed herein is the use of a compound selected from a compound of formula (I) disclosed herein, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cancer that responds to inhibition of IDO, wherein the cancer includes, but is not limited to, melanoma, thyroid cancer, barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, stomach cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, large intestine colon cancer, histiocytic lymphoma, lung adenocarcinoma, for example.

Also disclosed herein are compounds selected from the compounds of formula (I) disclosed herein, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in treating cancers that respond to inhibition of IDO, wherein the cancer includes, but is not limited to, e.g., melanoma, thyroid cancer, barrett's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, head and neck cancer, liver cancer, stomach cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic cancer, biliary tract cancer, non-small cell lung cancer, endometrial cancer, blood cancer, large intestine colon cancer, histiocytic lymphoma, lung adenocarcinoma.

A compound selected from compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, may be used alone or in combination with at least one other therapeutic agent for use in therapy. In some embodiments, a compound selected from compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can be used in combination with at least one additional therapeutic agent. The at least one additional therapeutic agent may, for example, be selected from an anti-hyperproliferative agent, an anti-cancer agent, and a chemotherapeutic agent. The at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein may be administered with the at least one other therapeutic agent in a single dosage form or as separate dosage forms. When administered as separate dosage forms, the at least one additional therapeutic agent may be administered prior to, concurrently with, or subsequent to the administration of the at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein.

"chemotherapeutic agents" are chemical compounds useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Suitable chemotherapeutic agents may, for example, be selected from: an agent that induces apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); a drug; a biological mimetic; an alkaloid; an alkylating agent; an anti-tumor antibiotic; an antimetabolite; a hormone; a platinum compound; monoclonal antibodies conjugated to anti-cancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g., interferons (such as IFN-a) and interleukins (such as IL-2)); adoptive immunotherapies; a hematopoietic growth factor; agents that induce tumor cell differentiation (e.g., all-trans retinoic acid); a gene therapy agent; antisense therapy agents and nucleotides; a tumor vaccine; and inhibitors of angiogenesis.

In a sixth aspect, disclosed herein is a pharmaceutical composition comprising a compound selected from a compound disclosed herein having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (e.g., carrier, diluent, or adjuvant).

Also disclosed herein are compositions comprising a compound selected from compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Compositions comprising a compound selected from compounds having (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, may be administered in a variety of known ways, for example orally, topically, rectally, parenterally, by inhalation spray or via an implanted depot, although the most suitable route in any given case will depend on the particular host, the nature and severity of the condition for which the active ingredient is being administered. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein may also be conveniently presented in unit dosage form and prepared by any of the methods well known in the art.

The compound selected from the group consisting of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, may be administered orally in solid dosage forms such as capsules, tablets, lozenges, dragees, granules and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. A compound selected from the compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, may also be administered parenterally in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Also useful for administering other dosage forms selected from compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as ointments, creams, drops, transdermal patches or powders for topical administration, as ophthalmic solution or suspension formation (i.e., eye drops) for ophthalmic administration, as aerosol spray or powder compositions for inhalation or intranasal administration, or as creams, ointments, sprays or suppositories for rectal or vaginal administration.

Gelatin capsules containing at least one compound disclosed herein and/or at least one pharmaceutically acceptable salt thereof and a powdered carrier (e.g., lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like) may also be used. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be made into sustained release products to provide continuous release of the drug over a period of time. Compressed tablets may be coated with a sugar or film coat to mask any unpleasant taste and protect the tablet from the air, or may be enteric coated to selectively disintegrate in the gastrointestinal tract.

Liquid dosage forms for oral administration may further comprise at least one pharmaceutical agent selected from coloring agents and flavoring agents to improve patient acceptance.

Generally, water, suitable oils, saline, aqueous dextrose (glucose), and related sugar solutions, and glycols (e.g., propylene glycol or polyethylene glycol) may be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may comprise a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if desired, at least one buffer material. Antioxidants (e.g., sodium bisulfite, sodium sulfite, or ascorbic acid), alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts and sodium EDTA may also be used as examples of suitable stabilizers. In addition, the parenteral solution may further comprise at least one preservative selected from, for example, benzalkonium chloride, methyl and propyl parabens, and chlorobutanol.

The pharmaceutically acceptable carrier is selected, for example, from carriers that are compatible with (and in some embodiments capable of stabilizing) the active ingredient of the composition and not deleterious to the subject to be treated. For example, a solubilizing agent, such as cyclodextrin (which can form a specific, more soluble complex with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) can be used as a pharmaceutical excipient for delivery of an active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (e.g., D & C yellow # 10). Suitable pharmaceutically acceptable carriers are described in the standard reference text Remington's Pharmaceutical Sciences, a.

A compound selected from the compounds disclosed herein having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can be further examined for its efficacy in treating cancer by in vivo assays. For example, at least one compound disclosed herein and/or at least one pharmaceutically acceptable salt thereof can be administered to an animal (e.g., a mouse model) having cancer, and the therapeutic effect thereof can be assessed. A positive result for one or more such tests is sufficient to augment the scientific knowledge base, and thus sufficient to demonstrate the utility of the tested compounds and/or salts. Based on these results, the appropriate dosage range and route of administration for an animal (e.g., human) can be determined.

For administration by inhalation, a compound selected from compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, may be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer. A compound selected from the compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, may also be delivered as a powder that may be formulated, and the powder composition may be inhaled by means of an insufflation powder inhaler device. An exemplary delivery system for inhalation may be a Metered Dose Inhalation (MDI) aerosol which may be formulated as a suspension or solution of a compound selected from compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein or stereoisomers thereof, or pharmaceutically acceptable salts thereof, in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons.

For ocular administration, a compound selected from the compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, disclosed herein, can be formulated with an appropriate weight percentage of a solution or suspension in an appropriate ophthalmic vehicle such that the compound selected from the compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), a stereoisomer thereof, and at least one pharmaceutically acceptable salt thereof, disclosed herein, is maintained in contact with the ocular surface for a sufficient time to allow the compound to penetrate to the cornea and interior regions of the eye.

Useful pharmaceutical dosage forms for administering a compound selected from compounds having the formulae (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4) disclosed herein or stereoisomers thereof, or pharmaceutically acceptable salts thereof, include, but are not limited to, hard and soft capsules, tablets, parenteral injections, and oral suspensions.

The dosage administered will depend on factors such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment (if any), the frequency of the treatment, and the desired nature of the effect. In general, the daily dose of the active ingredient may vary, for example, from 0.1 to 2000 mg/day. For example, administration of 10-500 mg/day one or more times is effective to achieve the desired result.

In some embodiments, a plurality of unit capsules are prepared by filling standard two-piece hard gelatin capsules each containing, for example, 100mg of a powdered compound selected from the compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or stereoisomers thereof, and pharmaceutically acceptable salts thereof, 150mg of lactose, 50mg of cellulose, and 6mg of magnesium stearate disclosed herein.

In some embodiments, a mixture of a compound selected from compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a digestible oil, such as soybean oil, cottonseed oil, or olive oil, may be prepared and injected with gelatin by a positive displacement pump to form a soft gelatin capsule containing 100mg of the active ingredient. The capsules were washed and dried.

In some embodiments, a plurality of tablets may be prepared by conventional procedures such that a dosage unit comprises, for example, 100mg of a compound selected from compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 0.2 mg of colloidal silicon dioxide, 5mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate coatings may be used to increase palatability or delay absorption.

In some embodiments, a parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of at least one compound and/or at least an enantiomer, diastereomer or pharmaceutically acceptable salt thereof in 10% by volume propylene glycol. The solution was made up to the desired volume with water for injection and sterilized.

In some embodiments, aqueous suspensions may be prepared for oral administration. For example, per 5ml of aqueous suspension may be used which comprises 100mg of finely dispersed compound selected from the group consisting of compounds having the formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or stereoisomers thereof, or pharmaceutically acceptable salts thereof, 100mg of sodium carboxymethylcellulose, 5mg of sodium benzoate, 1.0 g of sorbitol solution (u.s.p), and 0.025 ml of vanillin.

When a compound selected from the group consisting of compounds having formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered in steps or in combination with at least one other therapeutic agent, the same dosage form can generally be used. When drugs are administered in physical combination, the dosage form and route of administration should be selected according to the compatibility of the combined drugs. Thus, the term "co-administration" is understood to include the simultaneous or sequential administration of at least two agents, or alternatively the administration as a fixed dose combination of at least two active ingredients.

A compound selected from the compounds of formula (I), (Ia), (Ib-1), (Ib-2), (Ib-3), (Ib-4), stereoisomers thereof, and pharmaceutically acceptable salts thereof disclosed herein may be administered as the sole active ingredient or in combination with at least one second active ingredient selected from, for example, other active ingredients known to be useful in the treatment of cancer in a patient.

Examples of the invention

The following examples are intended to be purely exemplary and should not be considered as limiting in any way. Although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), some experimental errors and deviations should be accounted for. Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as Sigma Aldrich (Sigma-Aldrich), Alfa Aesar (Alfa Aesar) or TCI and were used without further purification unless otherwise indicated.

Unless otherwise stated, the reactions described below were carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent with a drying tube; the reaction flask was fitted with a rubber septum for introducing substrate and reagents via syringe; and oven drying and/or heat drying the glassware.

Unless otherwise indicated, column chromatographic purification was performed on a Biotage system with silica gel column (manufacturer: Dyax Corporation (Dyax Corporation)) or on silica SepPak columns (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica gel columns.

Recording on a Varian instrument operating at 400MHz¹H NMR spectrum. Using CDCl₃、CD₂Cl₂、CD₃OD、D₂O、d₆-DMSO、d₆-acetone or (CD)₃)₂CO as solvent and tetramethylsilane (0.00ppm) or residual solvent (CDCl)₃：7.25ppm；CD₃OD：3.31ppm；D₂O：4.79ppm；d₆-DMSO：2.50ppm；d₆-acetone: 2.05; (CD)₃)₂CO: 2.05) as reference standard¹H-NMR spectrum. When reporting multiple peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextuplex), m (multiplet), br (broad), dd (doublet), dt (doublet triplet). If a coupling constant is given, it is reported in hertz (Hz). All compound names except reagent were generated by ChemDraw version 12.0.

In the following examples, the following abbreviations are used:

AcOH acetic acid

Aq aqueous solution

Brine saturated aqueous sodium chloride solution

Bn benzyl group

BnBr benzyl bromide

Boc tert-butyloxycarbonyl

Cbz benzyloxycarbonyl

CH₂Cl₂Methylene dichloride

DMF N, N-dimethylformamide

Dppf 1, 1' -bis (diphenylphosphino) ferrocene

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

DCM dichloromethane

DIEA or DIPEA N, N-diisopropylethylamine

DIBAL-H diisobutylaluminum hydride

DMAP 4-N, N-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EA or EtOAc ethyl acetate

EtOH ethanol

Et₂O or ether ethyl ether

h or hr

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HBTU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HCl hydrochloric acid

Hex Hexane

HPLC high performance liquid chromatography

IPA 2-propanol

i-PrOH Isopropanol

mg of

mL of

Mmol millimole

MeCN acetonitrile

MeOH methanol

Min minute

MS or MS Mass Spectrometry

Na₂SO₄Sodium sulfate

PE Petroleum Ether

Ph³PO triphenyl phosphine oxide

PPA polyphosphoric acid

Rt Retention time

Rt or Rt Room temperature

TBAF tetrabutylammonium fluoride

TBSCl tert-butyldimethylsilyl chloride

TEA Triethanolamine

TFA trifluoroacetic acid

Tf₂O-Trifluoromethanesulfonic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

Ts p-toluenesulfonyl group

TBS tert-butyldimethylsilyl group

Microliter of μ L

Substituted benzo [ d ]]Synthesis of imidazoles

Example 1: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methyl-1H-benzo [ d]Tooth-stick Azole-5-carboxamides

Step 1: ethyl 2- (4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-en-1-yl) acetate

To a solution of ethyl 2- (4-oxocyclohexyl) acetate (18.4g, 100mmol, 1.00eq) dissolved in DCM (250ml) was added pyridine (9.48g, 120mmol, 1.20eq) and Tf₂O (42.15g, 150mmol, 1.50 eq). The mixture was stirred at room temperature overnight. The solution was washed with water (400ml), saturated ammonium chloride (400ml) and brine (400 ml). Combining the organic layers, passing over Na₂SO₄Dried, filtered and concentrated to dryness. The crude product (30.32g, 95% yield) was used in the next step without further purification.¹H NMR(CDCl₃)δ_H5.72(s,1H),4.15(q, J ═ 7.2Hz,2H),2.39-2.51(m,1H),2.28-2.38(m,4H),2.08-2.21(m,1H),1.87-1.98(m,2H),1.45-1.57(m,1H) and 1.27(t, J ═ 7.2Hz, 3H).

Step 2: ethyl 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-en-1-one- Yl) acetate ester

To a mixture of ethyl 2- (4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-en-1-yl) acetate (30.32g, crude, 96mmol, 1.00eq) dissolved in 1, 4-dioxane (400ml) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan) (26.8g, 106mmol, 1.10eq), CH₃COOK (38.02g, 192mmol, 2.00eq) and Pd (dppf) Cl₂(14.04g, 19.2mmol, 0.20 eq). The mixture was stirred at 95 ℃ under nitrogen for 18 hours. The solution was filtered and concentrated to dryness. Mixing the crude product (12)50g, 100% yield) was filtered through a pad of silica gel and washed with PE/EA ═ 6: 1. The filtrate was concentrated to dryness to give a black oil (33.2g, 112.3% yield), which was used in the next step without further purification.¹H NMR(CDCl₃)δ_H6.51(s,1H),4.13(q, J ═ 7.2Hz,3H),1.99-2.40(m,9H),1.68-1.94(m,3H) and 1.18-1.26(m, 12H).

And step 3: ethyl 2- (4- (6-fluoroquinolin-4-yl) cyclohex-3-en-1-yl) acetate

Ethyl 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-en-1-yl) acetate (33.2g, 110mmol, 1.10eq) was dissolved in 1, 4-dioxane (450ml) and 4-bromo-6-fluoroquinoline (22.5g, 100mmol, 1.00eq), Cs, were added₂CO₃(65g, 200mmol, 2.00eq) and Pd (dppf) Cl₂(14.62g, 20mmol, 0.20 eq). The mixture was stirred at 95 ℃ under nitrogen for 18 hours. The solution was filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (200g (PE/EA ═ 10/1 to 4/1)) to give a clear oil (12.02g, 34.8% yield).¹H NMR(CDCl₃)δ_H8.80(d, J ═ 4.4Hz,1H),8.15(dd, J ═ 9.2,5.6Hz,1H),7.62(dd, J ═ 10.0,2.8Hz,1H),7.49(m,1H),7.21(d, J ═ 4.4Hz,1H),5.81 to 5.87(m,1H),4.19(q, J ═ 7.2Hz,2H),2.23 to 2.57(m,6H),1.95 to 2.04(m,2H),1.53 to 1.65(m,1H) and 1.30(t, J ═ 7.2Hz, 3H).

And 4, step 4: ethyl 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) acetate

To a mixture of ethyl 2- (4- (6-fluoroquinolin-4-yl) cyclohex-3-en-1-yl) acetate (12.02g, 38mmol, 1.00eq) dissolved in MeOH (50ml) was added Pd/C (2.4g, w.t.20%) and the mixture was stirred at room temperature under a balloon of hydrogen overnight. However, the device is not suitable for use in a kitchenThe mixture was then filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (150g (PE/EA ═ 10/1 to 2/1)) to give a light yellow oil (8.51g, 70.3% yield).¹H NMR(CDCl₃)δ_H8.77-8.86(m,1H),8.15(dd, J ═ 9.2,5.6Hz,1H),7.66(dd, J ═ 10.4,2.4Hz,1H),7.44-7.52(m,1H),7.28-7.38(m,1H),4.16(q, J ═ 7.2Hz,2H),3.07-3.32(m,1H),2.45-2.53(m,2H),1.92-2.10(m,3H),1.53-1.89(m,6H) and 1.28(t, J ═ 7.2,4.0Hz, 3H).

And 5: 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) acetic acid

To a mixture of ethyl 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) acetate (8.51g, 27mmol, 1.00eq) dissolved in MeOH (20ml) and water (20ml) was added NaOH (1.61g, 40.5mmol, 1.50 eq). The mixture was stirred at room temperature for 2 hours. The solution was concentrated to 20mL and extracted with EA (20mL × 3) to remove impurities. The aqueous layer was concentrated to 5 ml. The aqueous layer was neutralized with 1N HCl to bring the pH to 7. The mixture was then added to water (200ml) and extracted with DCM/MeOH (20/1, 400ml × 3). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated to give the crude product, which was recrystallized in water to give the product (7.74 g).¹H NMR(DMSO-d₆)δ_H8.84(t, J ═ 4.4Hz,1H),8.11-8.25(m,1H),7.66(dd, J ═ 10.4,2.4Hz,1H),7.44-7.54(m,1H),7.28-7.40(m,1H),3.09-3.32(m,1H),2.31-2.64(m,3H),1.96-2.10(m,2H),1.72-1.91(m,4H),1.56-1.69(m,1H) and 1.29-1.45(m, 1H).

Step 6: (R) -3- (2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) acetyl) -4-phenyloxazolidin-2-one

To flask # a was added 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) acetic acid (7.74g, 27mmol, 1.00eq), THF (250ml), and TEA (8.5ml, 2.00 eq). The mixture was stirred at-78 ℃ for 0.5 h. Pivaloyl chloride (3.5ml, 1.95eq) was added dropwise to the flask under nitrogen. The mixture was then warmed to 0 ℃ and stirred for 1 hour.

To flask # b was added (R) -4-phenyloxazolidin-2-one (3.55g, 29mmol, 1.10eq) and THF (60 ml). The solution was cooled to-78 ℃ and N-BuLi (1.6N, 34ml, 2.00eq) was then added carefully. And the mixture was stirred at-78 ℃ for 0.5 hour.

Flask # a was then cooled to-78 ℃, and the contents of flask # b were added to flask # a via a cannula over the course of 15 minutes. After the addition was complete, the cold bath was removed and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (500ml) and extracted with EA (500ml × 3). Combining the organic layers, passing over Na₂SO₄Dried, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (100g (PE/EA ═ 4/1 to 1/1)) to give the product as a white solid, which was slurried in 2-methoxy-2-methylpropane to give the product as the cis product, and the mother liquor was a cis and trans mixture. Cis products¹HNMR(CDCl₃)δ_H 8.77-8.86(m,1H),8.24(s,1H),7.66(dd,J＝10.2,2.4Hz,1H),7.51(t,J＝8.4Hz,1H),7.28-7.45(m,6H),5.47(dd,J＝8.8,3.6Hz,1H),4.68-4.79(m,2H),4.26-4.35(m,1H),2.93-3.27(m,2H),2.41-2.56(m,1H),1.89-2.01(m,2H),1.67-1.84(m,4H),1.47-1.63(m,1H),1.28-1.39(m,1H)。

And 7: (R) -3- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoyl) -4-phenyloxa-nyl Oxazolidin-2-ones

To a solution of NaHMDS (1.0N, 14ml, 2.00eq) was added (R) -3- (2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) acetyl) -4-phenyloxazolidin-2-one (3.55g, 8mmol, 1.00eq) in THF (80ml) at-78 ℃. The mixture was warmed to-20 ℃ and stirred for 1 hour. The mixture was then cooled to-78 ℃ and addedMethyl iodide (7.50g, 3.3ml, 5.00 eq). The mixture was stirred at this temperature for 2 hours and quenched with saturated ammonium chloride solution (100ml) and extracted with EA (100ml × 3). Combining the organic layers, passing over Na₂SO₄Dried, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (100g (PE/EA ═ 4/1 to 1/1)) to give the product as a pale yellow solid (2.11g, 41% yield).¹H NMR(CDCl₃)δ_H 8.77-8.85(m,1H),8.09-8.18(m,1H),7.62-7.70(m,1H),7.44-7.50(m,1H),7.29-7.44(m,6H),5.38-5.52(m,2H),4.91-5.00(m,1H),4.66-4.79(m,2H),4.16-4.38(m,2H),2.10-2.20(m,1H),1.86-2.03(m,2H),1.65-1.83(m,4H),1.45-1.64(m,1H),1.12(t,J＝7.2Hz,2H)。

And 8: (R) -2- ((1S,4S) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) propanoic acid

To a solution of (R) -3- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoyl) -4-phenyloxazolidin-2-one (2.71g, 6mmol, 1.00eq) dissolved in THF (40ml) and water (10ml) at 0 ℃ H was added dropwise₂O₂(5 ml). The mixture was stirred at 0 ℃ for 1 hour. LiOH (2N, 6ml, 2.00eq) was then added to the mixture and stirred at room temperature for 4 hours. Subsequently LC/MS was performed and once the starting material had been consumed the mixture was washed at 0 ℃ by adding saturated Na₂SO₃Carefully quench. The pH was adjusted to 5-6 with 1N HCl, and the mixture was extracted with DCM/MeOH (40/1, 50 ml. times.4). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated to dryness to give a light yellow solid (1.02g, 55% yield).¹HNMR(CDCl₃)δ_H 8.82(d,J＝4.6Hz,1H),8.11-8.20(m,1H),7.63-7.72(m,1H),7.45-7.53(m,1H),7.27-7.33(m,1H),3.12-3.33(m,1H),2.34-2.49(m,1H),1.57-2.14(m,9H),1.20-1.29(m,3H)。

And step 9: 3-amino-4- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamido) -N-methylbenzene Formyl radicalsAmines as pesticides

To a solution of (R) -2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionic acid (100mg, 0.33mmol) in DMF (10mL) was added Pybop (250mg, 0.48mmol), DIPEA (200mg, 1.55mmol) and N⁴-methylbenzene-1, 2, 4-triamine (100mg, 0.73mmol) and heated to 60 ℃ for 4 hours. After cooling, EA was added, washed with water and brine, over Na₂SO₄Dried, concentrated and purified by silica gel (DCM: MeOH ═ 5:100-10:100) to give compounds 1-13(20 mg).

Step 10: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methyl-1H-benzo [ d] Imidazole-5-carboxamides

Will be provided withCompounds 1 to 13(20mg) solution in HOAc (4mL) was stirred at 110 deg.C for 16 h, then the solvent was evaporated. The crude residue was dissolved with EA (50mL) and saturated NaHCO₃The solution (50mL) was washed. The organic phase was separated and purified by preparative HPLC to give the title compound.¹H NMR(400MHz,DMSO-d)δ_H 8.79(d,J＝4.7Hz,1H),8.09-8.06(m,2H),7.89-7.86(m,1H),7.77-7.46(m,4H),3.56-3.39(m,2H),2.94(s,3H),2.28-2.14(m,2H),2.00-1.90(m,4H),1.78-1.69(m,2H),1.47-1.45(m,3H),1.31(d,J＝12.1Hz,1H)。

Example 2 (compound 2) was prepared by a similar procedure as example 1.

Example 2: 2- ((R) -1- ((1S,4S) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-isopropyl-1H-benzene And [ d ]]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.40(d,J＝10.6Hz,1H),8.87(d,J＝4.4Hz,1H),8.15-8.08(m,3H),7.98(dd,J＝11.0,2.7Hz,1H),7.92(s,0.5H),7.71-7.62(m,2H),7.58(d,J＝4.5Hz,1H),7.55-7.43(m,1H),4.14-4.09(m,1H),3.42-3.42(m,2H),2.20-2.00(m,2H),1.95-1.70(m,4H),1.69-1.50(m,2H),1.36(d,J＝6.7Hz,3H),1.17(d,J＝6.5Hz,6H)。

Example 3: n- (tert-butyl) -2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H- Benzo [ d ] carbonyl]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δH 12.39(s,1H),8.87(d,J＝4.5Hz,1H),8.14-7.82(m,3H),7.72-7.37(m,5H),3.45-3.40(m,2H),2.19-1.96(m,2H),1.95-1.72(m,4H),1.67-1.54(m,2H),1.43-1.34(m,12H),1.16-1.13(m,1H)。

Example 4: n-cyclobutyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzene And [ d ]]Imidazole-6-carboxamides

Steps 1a and 1 b: 4-amino-N-cyclobutyl-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl Amino) benzamides

To a solution of (R) -2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionic acid (400mg, 1.33mmol) in DCM (10mL) was added dropwise DMF (1 drop) and oxalyl chloride (200mg, 1.55mmol), the mixture was stirred at room temperature for 2 hours and concentrated to give crude 2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride. To a solution of 3, 4-diamino-N-cyclobutylbenzamide and DIPEA in THF at 0 deg.C was added dropwise a solution of 2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride in THF, the reaction mixture was stirred at 0 deg.C for 30min, the reaction mixture was concentrated, EA was added, washed with water and brine, over Na₂SO₄Dried, concentrated, and purified over silica gel to give 4-amino group-N-cyclobutyl-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) benzamide.

Step 2: n-cyclobutyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d] Imidazole-6-carboxamides

Heating a solution of 4-amino-N-cyclobutyl-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) benzamide in HOAc to 110 ℃ for 8 hours, cooling, concentrating the mixture, adding saturated NaHCO₃Aqueous solution, extraction with EA, washing of the EA layer with brine, over Na₂SO₄Dried, concentrated and purified by silica gel to give N-cyclobutyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxamide.¹H NMR(400MHz,DMSO-d)δ_H 12.43(s,1H),8.87(d,J＝4.5Hz,1H),8.52(s,1H),8.12-8.08(m,1H),7.98(dd,J＝11.0,2.6Hz,1H),7.69-7.64(m,2H),7.59-7.47(m,2H),4.44(dd,J＝16.3,8.2Hz,1H),3.45-3.41(m,Hz,2H),2.28-1.98(m,6H),1.95-1.73(m,4H),1.72-1.52(m,4H),1.36(d,J＝6.8Hz,3H),1.17(d,J＝12.4Hz,1H)。

And step 3: n-cyclohexyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzene And [ d ]]Imidazole-6-carboxamides

By using preparative HPLC at CHIRALPAK IC (Hex (8mM NH)₃MeOH): EtOH 70:30 as eluent) 53mg of compound example 4 was separated from 65mg of compound 4-4, and the desired enantiomer eluted at a retention time of 2.483 min.¹H NMR(MeOH-d6)δ_H 12.46(s,1H),8.87(d,J＝4.5Hz,1H),8.53(s,1H),8.10(dd,J＝9.2,5.8Hz,1H),8.02-7.93(m,1H),7.69-7.64(m,2H),7.59(d,J＝4.3Hz,1H),7.50(s,1H),4.44(dd,J＝16.0,7.9Hz,1H),3.45-3.39(m,2H),2.28-2.00(m,7H),1.96-1.74(m,4H),1.71-1.50(m,4H),1.36(d,J＝6.8Hz,3H),1.16(d,J＝11.7Hz,1H)。

Example 5: n-cyclopentyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzene And [ d ]]Imidazole-6-carboxamides

2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (90mg, 0.21mmol), cyclopentylamine (35mg, 0.4mmol), PyBop (160mg, 0.31mmol) and Et₃A solution of N (130mg, 1.3mmol) in DCM (10mL) was stirred at room temperature for 16 h, the reaction mixture was concentrated, EA was added, washed with water and brine, and Na₂SO₄Dried, concentrated and purified by silica gel to give N-cyclopentyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxamide.¹H NMR(400MHz,DMSO-d)δ_H12.42(s,1H),8.87(d,J＝4.5Hz,1H),8.19(s,1H),8.10(dd,J＝9.2,5.8Hz,1H),7.98(dd,J＝11.0,2.7Hz,1H),7.68-7.64(m,2H),7.58(d,J＝4.6Hz,1H),7.50-7.48(m,1H),4.24(dd,J＝13.6,6.9Hz,1H),3.45-3.39(m,2H),3.01(td,J＝6.6,4.0Hz,1H),2.16-2.03(m,2H),1.91-1.81(m,4H),1.76-1.67(m,5H),1.61-1.53(m,4H),1.36(d,J＝6.8Hz,3H),1.20-1.12(m,1H)。

Example 6 (Compound 6) was prepared by a procedure similar to example 5

Example 6: n-cyclohexyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzene And [ d ]]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.43(s,1H),8.87(d,J＝4.5Hz,1H),8.10(dd,J＝9.2,5.9Hz,2H),7.98(dd,J＝11.0,2.7Hz,1H),7.71-7.61(m,2H),7.58(d,J＝4.6Hz,1H),7.49-7.47(m,1H),3.77(s,1H),3.45-3.41(m,2H),2.19-2.00(m,2H),1.97-1.76(m,6H),1.72-1.70(m,3H),1.66-1.51(m,3H),1.36(d,J＝6.9Hz,3H),1.31-1.28(m,3H),1.17-1.14(m,2H)。

Example 7: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methoxy-1H-benzo [ d] Imidazole-6-carboxamides

Steps 1a and 1 b: ethyl 4-amino-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) -propionamide Yl) benzoic acid esters

To a solution of 2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionic acid (4.0g, 13.3mmol) in DCM (100mL) was added dropwise DMF (1 drop) and oxalyl chloride (2.5mL, 30mmol), the mixture was stirred at room temperature for 2 hours and concentrated to give crude 2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride (step 1 a). To a solution of ethyl 3, 4-diaminobenzoate (2.5g, 14mmol) and DIPEA (3.8g, 29mmol) in THF (150mL) at 0 deg.C was added dropwise a solution of 2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride in THF (50mL), the reaction mixture was stirred at 0 deg.C for 30min, the reaction mixture was concentrated, EA was added, washed with water and brine, over Na₂SO₄Dried, concentrated and purified by silica gel to give 4.3g of ethyl 4-amino-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) benzoate.

Step 2: ethyl 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole- 6-formic acid ester

A solution of ethyl 4-amino-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) benzoate (4.3g) in HOAc (150mL) was heated to 110 ℃ for 8 hours, after cooling, the mixture was concentrated, saturated NaHCO was added₃Aqueous solution, extraction with EA, layer EA with brineWashing with Na₂SO₄Dried, concentrated and purified by silica gel to give ethyl 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid esters.¹H NMR(400MHz,DMSO-d)δ_H 8.87(d,J＝4.5Hz,1H),8.13-8.08(m,2H),7.99(dd,J＝10.9,2.5Hz,1H),7.82(dd,J＝8.5,1.4Hz,1H),7.67(td,J＝8.7,2.6Hz,1H),7.63-7.55(m,2H),4.32(q,J＝7.1Hz,2H),3.55-3.42(m,2H),2.18-2.15(m,1H),2.11-2.01(m,1H),1.95-1.73(m,4H),1.71-1.52(m,2H),1.38(d,J＝6.8Hz,3H),1.34(t,J＝7.1Hz,3H),1.18-1.14(m,1H)。

And step 3: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]-imidazole-6- Formic acid

Reacting ethyl 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxylate (200mg, 0.45mmol) and LiOH. H₂O (260mg, 6.2mmol), NaOH (200mg, 5.0mmol) in THF/MeOH/H₂The solution in O (10mL/10mL/10mL) was stirred at room temperature for 48H, the reaction mixture was concentrated, the pH of the residue was adjusted to 6 with 1N aqueous HCl, a white solid was collected and dried in vacuo to give 160mg of crude 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d [ -d]Imidazole-6-carboxylic acid.

And 4, step 4: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methoxy-1H-benzo [ d] Imidazole-6-carboxamides

Reacting 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]A solution of imidazole-6-carboxylic acid (130mg, 0.31mmol), methoxylamine hydrochloride (50mg, 0.6mmol), PyBop (280mg, 0.54mmol) and DIPEA (0.5mL, 2.9mmol) in DCM (15mL) was stirred at room temperatureAfter 16 h, the reaction mixture was concentrated, EA was added, washed with water and brine, and washed with Na₂SO₄Dried, concentrated and purified by silica gel to give 35mg of 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methoxy-1H-benzo [ d]Imidazole-6-carboxamide.¹H NMR(400MHz,DMSO-d)δ_H 12.52(s,1H),11.64(s,1H),8.87(d,J＝4.4Hz,1H),8.10(dd,J＝9.2,5.8Hz,1H),7.98(dd,J＝11.0,2.4Hz,1H),7.91(s,1H),7.67(dd,J＝11.6,5.6Hz,1H),7.62-7.46(m,3H),3.72(s,3H),3.46-3.41(m,6.6Hz,2H),2.16-2.03(m,2H),1.96-1.71(m,4H),1.67-1.55(m,2H),1.36(d,J＝6.7Hz,3H),1.17-1.14(m,1H)。

Examples 8 to 10b (compounds 8 to 10b) were prepared by a procedure similar to example 7.

Example 8: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N, N-dimethyl-1H-benzo [d]Imidazole-5-carboxamides

¹H NMR(400MHz,cd3od)δ_H 8.69(d,J＝4.7Hz,1H),7.98(dd,J＝9.2,5.6Hz,1H),7.79(dd,J＝10.6,2.6Hz,1H),7.62-7.44(m,3H),7.21(d,J＝8.3Hz,1H),3.48-3.28(m,2H),3.03(s,3H),2.96(s,3H),2.16-2.09(m,2H),2.00-1.73(m,4H),1.66-1.60(m,2H),1.37(d,J＝6.8Hz,3H),1.22(d,J＝11.8Hz,1H)。

Example 9: n-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzene And [ d ]]Imidazole-6-carboxamides

1H NMR(400MHz,DMSO-d)δ_H 12.42(d,J＝11.4Hz,1H),8.86(d,J＝4.5Hz,1H),8.37-8.33(m,1H),8.10(dd,J＝9.2,5.8Hz,1H),8.04(s,0.5H),7.98(dd,J＝11.0,2.7Hz,1H),7.90(s,0.5H),7.70-7.40(m,4H),3.48-3.36(m,2H),2.88-2.83(m,1H),2.16-2.03(m,2H),1.95-1.73(m,4H),1.69-1.51(m,2H),1.36(d,J＝6.8Hz,3H),1.17-1.14(m,1H),0.69-0.68(m,2H),0.59-0.57(m,2H)。

Example 10: n-cyclobutyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl- 1H-benzo [ d ]]Imidazole-5-carboxamides

Step 1: 4-acetamido-3-methylbenzoic acid

To a solution of 4-amino-3-methylbenzoic acid (10g, 66mmol) in DCM (50mL) at 0 deg.C was added Et₃N (13g) and Ac₂O (8g, 8 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. Adding H to the mixture₂O (50mL) and the mixture was extracted with EA (50mL × 2). The organic phase was separated, washed with brine (100mL) and concentrated to give 4-acetamido-3-methylbenzoic acid as a white solid (10g), which was used in the next step without further purification.

Step 2: 4-acetamido-3-methyl-5-nitrobenzoic acid

At 0 deg.C, adding HNO₃(20ml) was slowly added dropwise to H₂SO₄(20 ml). At this temperature, the mixture was stirred for 10min, then 4-acetamido-3-methylbenzoic acid (10g) was added to the mixture, and stirred at 0 ℃ for another 1 h. After completion of the reaction, the mixture was dropped into ice with stirring. The solid was filtered and dried to give 4-acetamido-3-methyl-5-nitrobenzoic acid (9 g).

And step 3: methyl 4-acetamido-3-methyl-5-nitrobenzoate

To a solution of 4-acetamido-3-methyl-5-nitrobenzoic acid (5g, 21mmol) in DMF (20ml) was added CH₃I (2.98g, 1.2ml) and K₂CO₃(5.8g, 42 mmol). The mixture was stirred at room temperature overnight. Adding H to the mixture₂O (60mL) and the mixture was extracted with EA (60mL × 2). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated to give the crude product which was further purified by combiflash (eluting with EA: PE ═ 1:0 to 1: 1) to give methyl 4-acetamido-3-methyl-5-nitrobenzoate (3.7 g).

And 4, step 4: methyl 4-amino-3-methyl-5-nitrobenzoate

To a solution of methyl 4-acetamido-3-methyl-5-nitrobenzoate (3.7g) in MeOH (50ml) was added SOCl₂(6 ml). The mixture was stirred at 65 ℃ overnight. The solvent was removed under vacuum. The residue was washed with Na₂CO₃Basification to pH>7 and extracted with EA (50mL × 3). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated to give methyl 4-amino-3-methyl-5-nitrobenzoate (3.4g), which was used in the next step without further purification.

And 5: methyl 3, 4-diamino-5-methylbenzoate.

To methyl 4-amino-3-methyl-5-nitrobenzoate (3.4g, 16.2mmol) in EtOH (60mL) and H₂To a suspension in O (10ml) were added iron powder (4.5g, 87mmol) and NH₄Cl (6.9g, 129.6 mmol). The mixture was heated at 70 ℃ under N₂Stirring for 8 h. Filtering the mixture and filteringAnd (4) concentrating the solution. Adding NaHCO to the mixture₃(aqueous solution, 50mL) and the mixture was extracted with EA (50mL × 2). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated to give methyl 3, 4-diamino-5-methylbenzoate (2.0g), which was used in the next step without further purification.

Step 6: methyl 4-amino-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamido) -5-me-thyl Benzoic acid ester

To a solution of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionic acid (301mg, 1.0mmol) in DMF (20mL) was added methyl 3, 4-diamino-5-methylbenzoate (217mg, 1.2mmol), HATU (456mg, 1.2mmol), and Et₃N (204mg, 2.0mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, EA was added and the mixture was washed with water and brine, over Na₂SO₄Dried and concentrated to give methyl 4-amino-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) -5-methylbenzoate (400mg), which was used in the next step without further purification.

And 7: methyl 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [d]5-Carboxylic acid imidazole ester

A solution of methyl 4-amino-3- (2- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) -5-methylbenzoate (400mg) in HOAc (20mL) was heated to 110 ℃ for 8 hours, after cooling, the mixture was concentrated, saturated NaHCO was added₃Aqueous solution and extraction with EA, washing the EA layer with brine, over Na₂SO₄Dried, concentrated, and purified by silica gel to give methyl 2- (1- ((1s,4s) -4- (6-fluoroquinoline-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]Imidazole-5-carboxylate (120 mg).

And step 3: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]Tooth-stick Azole-5-carboxylic acid

Reacting methyl 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]Imidazole-5-carboxylate (110mg, 0.25mmol) and LiOH. H₂O (53mg, 1.25mmol) in MeOH/H₂The solution in O (10mL/2mL) was stirred at room temperature for 48H, the reaction mixture was concentrated, the pH of the residue was adjusted to 6 with 1N aqueous HCl, a white solid was collected and dried in vacuo to give 60mg of crude 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]Imidazole-5-carboxylic acid.

And 8: n-cyclobutyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H- Benzo [ d ] carbonyl]Imidazole-5-carboxamides

Reacting 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]A solution of imidazole-5-carboxylic acid (60mg, 0.14mmol), cyclobutylamine (12mg, 0.168mmol), HATU (64mg, 0.168mmol) and 4-methylmorpholine (0.5mL) in DMF (10mL) was stirred at room temperature for 16 h, the reaction mixture was concentrated, EA was added, washed with water and brine, Na over Na₂SO₄Dried, concentrated and purified by silica gel to give 50mg of N-cyclobutyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]Imidazole-5-carboxamide.¹H NMR(400MHz,DMSO-d6)δ_H 12.33-12.35(m,1H),8.86(d,J＝8.0Hz,1H),8.47(d,J＝8.0Hz,1H),8.08-8.11(m,1H),7.96-7.99(m,1H),7.65-7.69(m,2H),7.58-7.59(m,1H),7.48(s,1H),4.39-4.46(m,1H),3.41-3.48(m,2H),2.52(s,3H),2.15-2.20(m,3H),2.05-2.09(m,3H),1.77-1.93(m,4H),1.55-1.66(m,4H),1.36(d,J＝8.0Hz,3H),and 1.16-1.23(m,1H)。[M+H]+＝485。

Examples 10a and 10 b: n-cyclobutyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethane Radical) -7-methyl-1H-benzo [ d]Imidazole-5-carboxamide and N-cyclobutyl-2- ((S) -1- ((1S,4R) -4- (6-fluoroquinoline-4-) Yl) cyclohexyl) ethyl) -7-methyl-1H-benzo [ d]Imidazole-5-carboxamides

Prepared HPLC was used at CHIRAL ART Cellulose-SB (HEX (8mmol/L NH)₃MeOH): IPA 80:20 as eluent) were separated from compounds 10a and 10 b. The first enantiomer 10a eluted at a retention time of 3.683min (6.82mg),¹H NMR(DMSO-d6)δ_H12.26-12.34(m,1H),8.86(d, J ═ 8.0Hz,1H),8.46-8.48(m,1H),8.08-8.11(m,1H),7.96-7.99(m,1H),7.74-7.90(m,1H),7.59-7.69(m,2H),7.47(s,1H),4.40-4.46(m,1H),3.41-3.44(m,2H),2.52(s,3H),2.15-2.20(m,3H),2.04-2.07(m,3H),1.58-1.89(m,8H),1.36(d, J ═ 8.0Hz,3H), and 1.19-1.29(m, 1H). [ M + H ]]485 +. And the other enantiomer 10b (10.33mg) eluted at a retention time of 4.778min,¹H NMR(DMSO-d6)δ_H12.26-12.34(m,1H),8.87(d, J ═ 8.0Hz,1H),8.46-8.48(m,1H),8.08-8.11(m,1H),7.96-7.99(m,1H),7.74-7.90(m,1H),7.59-7.69(m,2H),7.47(s,1H),4.42-4.46(m,1H),3.41-3.44(m,2H),2.52(s,3H),2.15-2.20(m,3H),2.04-2.07(m,3H),1.58-1.89(m,8H),1.36(d, J ═ 8.0Hz,3H), and 1.17-1.24(m, 1H). [ M + H ]]+＝485。

Example 11: 2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- (oxetan-3-yl) -1H-benzene And [ d ]]Imidazole-6-carboxamides

Step 1: 2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid

Reacting ethyl 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]A solution of imidazole-6-carboxylate (5.0g, 11.2mmol) in 4N aqueous HCl (150mL) was heated to 80 ℃ for 5 hours, the reaction mixture was concentrated, the pH of the residue was taken up with saturated NaHCO₃The aqueous solution is adjusted to 6, extracted with EA, the EA layer is concentrated and purified over silica gel to give 2.0g of 2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid.

Step 2: 2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- (oxetan-3-yl) -1H-benzo [d]Imidazole-6-carboxamides

Reacting 2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-6-carboxylic acid (100mg, 0.24mmol), oxetan-3-amine (36mg, 0.5mmol), HATU (150mg, 0.39mmol) and Et₃A solution of N (100mg, 1.0mmol) in DCM (10mL) was stirred at room temperature for 16 h, the reaction mixture was concentrated, EA was added, washed with water and brine, and Na₂SO₄Dried, concentrated, and purified by silica gel and preparative HPLC to give the desired product.¹H NMR(400MHz,DMSO-d)δ_H 12.47(d,J＝13.0Hz,1H),9.01(dd,J＝19.5,6.3Hz,1H),8.87(d,J＝4.5Hz,1H),8.16-7.95(m,3H),7.68(m,2H),7.53(m,2H),5.03(m,1H),4.77(t,J＝6.7Hz,2H),4.62(td,J＝6.4,2.5Hz,2H),3.43(m,2H),2.19-1.53(m,8H),1.37(d,J＝6.8Hz,3H),1.17(m,1H)。

Example 12: 2- ((R) -1- ((1R,4R) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- (2-methoxyethyl) Base)-1H-benzo [ d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.39(d,J＝13.0Hz,1H),8.79(d,J＝4.6Hz,1H),8.43(m,1H),8.02(m,3H),7.72-7.38(m,4H),3.52-3.40(m,4H),3.28(s,3H),2.94(m,1H),1.98-1.41(m,8H),1.40(d,J＝7.2Hz,3H)。

Example 13: 2- ((R) -1- ((1S,4S) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- (2-methoxyethyl) Radical) -1H-benzo [ d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.43(d,J＝13.3Hz,1H),8.86(d,J＝4.5Hz,1H),8.42(m,1H),8.14-7.91(m,3H),7.71-7.42(m,4H),3.49-3.37(m,6H),3.27(s,3H),2.10(m,2H),1.95-1.53(m,6H),1.36(d,J＝6.8Hz,3H),1.16(m,1H)。

Example 14: 2- ((R) -1- ((1S,4S) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-phenyl-1H-benzo [d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.50(d,J＝17.1Hz,1H),10.19(d,J＝19.7Hz,1H),8.80(d,J＝4.5Hz,1H),8.30-7.94(m,3H),7.81(m,3H),7.60(m,2H),7.44(d,J＝4.7Hz,1H),7.35(t,J＝7.7Hz,2H),7.09(t,J＝7.3Hz,1H),3.01-2.91(m,1H),2.00-1.23(m,12H)。

Example 15: 2- ((R) -1- ((1R,4R) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-phenyl-1H-benzo [d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.53(d,J＝20.5Hz,1H),10.18(d,J＝16.3Hz,1H),8.87(d,J＝4.4Hz,1H),8.28-7.93(m,3H),7.84-7.73(m,3H),7.71-7.50(m,3H),7.34(t,J＝7.5Hz,2H),7.08(t,J＝7.2Hz,1H),3.44(m,2H),2.22-1.52(m,8H),1.38(d,J＝6.7Hz,3H),1.23(m,1H)。

Example 16: 2- ((R) -1- ((1S,4S) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- ((1-Hydroxycyclobutan Yl) methyl) -1H-benzo [ d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.32(s,1H),8.79(d,J＝4.6Hz,1H),8.07(dd,J＝9.0,5.9Hz,1H),7.98(m,2H),7.66(m,2H),7.43(m,2H),4.90(s,1H),4.17(d,J＝10.8Hz,1H),3.98(d,J＝8.8Hz,1H),3.55(d,J＝16.7Hz,1H),2.98-2.87(m,2H),1.95-1.50(m,6H),1.38(d,J＝6.8Hz,3H)

Example 17: 2- ((R) -1- ((1R,4R) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- ((1-hydroxycyclobutane) Yl) methyl) -1H-benzo [ d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.46(s,1H),8.85(d,J＝4.3Hz,1H),8.09(dd,J＝9.0,5.9Hz,1H),8.03-7.89(m,2H),7.76-7.61(m,2H),7.57(d,J＝4.0Hz,1H),7.45(dd,J＝35.0,8.4Hz,1H),4.96-4.84(m,2H),4.17(d,J＝10.6Hz,1H),3.98(d,J＝10.7Hz,1H),3.55(d,J＝16.8Hz,1H),3.47-3.39(m,2H),3.34(d,J＝5.4Hz,2H),3.25(d,J＝16.9Hz,1H),2.09(m,2H),1.95-1.50(m,6H),1.35(d,J＝6.6Hz,3H),1.17(m,1H)。

Example 18: 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- (4-methoxycyclo ring Hexyl) -1H-benzo [ d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.41(ds,1H),8.87(d,J＝4.5Hz,1H),8.17-7.90(m,4H),7.70-7.42(m,4H),3.77(m,1H),3.42(m,2H),3.24(s,3H),3.11(m,1H),2.18-1.52(m,14H),1.36(d,J＝6.6Hz,3H),1.23(m,1H)。

Example 19: 2- ((R) -1- ((1R,4R) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N- (4-methoxycyclo Hexyl) -1H-benzo [ d]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.41(ds,1H),8.87(d,J＝4.5Hz,1H),8.17-7.90(m,4H),7.70-7.42(m,4H),3.77(m,1H),3.42(m,2H),3.24(s,3H),3.11(m,1H),2.18-1.52(m,14H),1.36(d,J＝6.6Hz,3H),1.23(m,1H)。

Example 20: n-cyclopropyl-6-fluoro-2- (1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H- Benzo [ d ] carbonyl]Imidazole-5-carboxamides

Step 1: methyl 6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-5- Formic acid esters

A mixture of 2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoic acid (600mg, 2.0mmol) and methyl 4, 5-diamino-2-fluorobenzoate (360mg, 2.0mmol) in PPA (15mL) was heated to 130 ℃ for 2 hours. The reaction mixture was poured into aqueous NaOH (5%, 100mL), extracted with EA, and the EA layer was Na₂SO₄Dried, concentrated and purified by silica gel to giveMethyl 6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]imidazole-5-A Acid esters。

Step 2: 6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-5-carboxylic acid

Reacting methyl 6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-5-carboxylate (300mg, 0.67mmol) and NaOH (200mg, 5.0mmol) in MeOH/H₂The solution in O (20mL/20mL) was stirred at room temperature for 48H, the reaction mixture was concentrated, the pH of the residue was adjusted to 5 with 1N HCl aqueous solution, a white solid was collected and dried in vacuo to afford 6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d [ -d]Imidazole-5-carboxylic acid.

And step 3: n-cyclopropyl-6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Tooth-stick Azole-5-carboxamides

Reacting 6-fluoro-2- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-5-carboxylic acid (80mg, 0.17mmol), cyclopropylamine (15mg, 0.2mmol), Hybop (140mg, 0.27mmol) and Et₃A solution of N (150mg, 1.5mmol) in DMF (8mL) was stirred at room temperature for 16 h, EA was added, washed with water and brine, and Na₂SO₄Dried, concentrated, and purified by silica gel and preparative HPLC to give N-cyclopropyl-6-fluoro-2- (1- (4)- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-benzo [ d]Imidazole-5-carboxamide.¹H NMR(400MHz,DMSO-d)δ_H 12.48(d,1H),8.86(d,J＝4.4Hz,1H),8.20(s,1H),8.09(m,1H),7.97(d,J＝10.8Hz,1H),7.55-7.70(m,3H),7.27-7.39(dd,1H),3.42(m,2H),2.85(m,1H),1.54-2.14(m,9H),1.34(d,J＝5.6Hz,3H),0.68(m,2H),0.55(m,2H)。

Example 21: n-cyclopropyl-4, 5-difluoro-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) - 1H-benzo [ d ]]Imidazole-6-carboxamides

¹H NMR(400MHz,DMSO-d)δ_H 12.8(s,1H),8.86(m,1H),8.37(m,1H),8.10(m,1H),7.98(m,1H),6.66(m,1H),7.59(m,1H),7.42(m,1H),3.42(m,2H),2.85(m,1H),1.55-2.16(m,10H),1.36(d,J＝6.8Hz,3H),0.70(m,2H),0.55(m,2H)。

Example 22: n-cyclopropyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-imidazo [4,5-c]Pyridine-6-carboxamides

Step 1: methyl 2- (1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-imidazo [4,5- c]6-Pyridinecarboxylic acid ester

A mixture of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoic acid (200mg, 0.664mmol) and methyl 4, 5-diaminopicolinate (130mg, 0.863mmol) in PPA (5ml) was stirred at 125 ℃ overnight. After completion of the reaction as determined by LCMS, H was added to the mixture₂O (100 ml). With NaHCO₃The residue was adjusted to pH 7-8 with saturated aqueous solution, filtered to give the crude product (276mg) as a yellow solid, 20mg of which was purified by preparative HPLC to give 7.41mg of the desired product as a white solid.¹H NMR(400MHz,DMSO)δ13.07(d,J＝20.0Hz,1H),9.00-8.78(m,2H),8.22(d,J＝32.0Hz,1H),8.09(dd,J＝9.2,6.0Hz,1H),7.98(d,J＝8.8Hz,1H),7.71-7.63m,1H),7.59(d,J＝4.4Hz,1H),3.88(s,3H),3.53(dd,J＝10.4,6.8Hz,1H),3.43(s,1H),2.18(d,J＝10.0Hz,1H),2.06(d,J＝10.8Hz,1H),1.95-1.71(m,4H),1.71-1.52(m,2H),1.38(d,J＝6.4Hz,2H),1.14(d,J＝10.0Hz,1H)。[M+1]⁺357。

Step 2: 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-imidazo [4,5- c]Pyridine-6-carboxylic acid

To methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) -ethyl) -1H-imidazo [4,5-c]To a solution of pyridine-6-carboxylate (250mg, 0.578mmol) in EtOH (5ml) were added KOH (64.8mg, 1.157mmol) and water (3 ml). The mixture was stirred at 80 ℃ for 2 h. After completion of the reaction as determined by LCMS, EtOH was removed under vacuum and 10ml water was added. The pH of the aqueous layer of the residue was adjusted to 6 with HCl (1M) and filtered to give 208mg of the desired product as a yellow solid.¹H NMR(400MHz,dmso)δ8.84(d,J＝3.6Hz,2H),8.19(s,1H),8.09(dd,J＝9.2,6.0Hz,1H),7.98(dd,J＝11.2,2.4Hz,1H),7.70-7.62(m,1H),7.59(d,J＝4.0Hz,1H),3.54(dd,J＝10.4,6.8Hz,2H),3.42(s,2H),2.19(d,J＝9.2Hz,1H),2.06(d,J＝12.0Hz,1H),1.96-1.72(m,4H),1.71-1.50(m,2H),1.38(d,J＝6.8Hz,3H),1.15(d,J＝12.8Hz,1H)。[M+1]⁺419。

And step 3: n-cyclopropyl-2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-imidazo [4,5-c]Pyridine-6-carboxamides

To 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -1H-imidazo [4, 5-c) at room temperature]To a solution of pyridine-6-carboxylic acid (100mg, 0.239mmol) in DCM (5mL) was added HATU (109mg, 0.289mmol), TEA (48.3mg, 0.487 mmol). Cyclopropylamine (20.4mg, 0.358mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction as determined by LCMS, the reaction mixture was taken up with H₂O (10mL) was quenched and extracted with EA (10mL × 2). The organic layer was separated and washed with brine (20mL) and concentrated. The residue was purified by preparative HPLC to give the title compound.¹H NMR(400MHz,dmso)δ12.97(s,1H),8.91-8.74(m,2H),8.65(s,1H),8.16-8.04(m,2H),8.00-7.91(m,1H),7.72-7.54(m,2H),3.58-3.49(m,1H),3.43(s,1H),3.14-3.07(m,1H),2.96-2.88(m,1H),2.17(d,J＝10.0Hz,1H),2.05(d,J＝8.4Hz,1H),1.97-1.72(m,4H),1.72-1.53(m,2H),1.38(d,J＝6.8Hz,3H),0.75-0.63(m,4H)。[M+1]⁺458。

Examples 22a and 22 b: n-cyclopropyl-2- ((S) -1- ((1S,4R) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethane Radical) -1H-imidazo [4,5-c]Pyridine-6-carboxamide and N-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinoline-4-) Yl) cyclohexyl) ethyl) -1H-imidazo [4,5-c]Pyridine-6-carboxamides

Preparative HPLC was used at CHIRALPAK IC (Hex (8mM NH)₃MeOH): ETOH 60:40 as eluent) each enantiomer of example 22 (racemates 22a and 22b) was separated. The first enantiomer 22a (12.77mg) eluted at a retention time of 2.515min,¹H NMR(400MHz,dmso)δ12.96(s,1H),8.90-8.70(m,2H),8.68-8.54(m,1H),8.20-8.05(m,2H),7.98(d,J＝9.0Hz,1H),7.67(t,J＝7.4Hz,1H),7.59(d,J＝3.6Hz,1H),3.61-3.37(m,2H),2.92(d,J＝4.4Hz,1H),2.18(s,1H),2.05(d,J＝11.6Hz,1H),1.95-1.72(m,4H),1.72-1.54(m,2H),1.38(d,J＝6.4Hz,3H),1.15(d,J＝11.6Hz,1H),0.75-0.63(m,4H)。[M+1]⁺458. and the other enantiomer 22b (14.47mg) eluted at a retention time of 5.021min,¹H NMR(400MHz,dmso)δ12.96(s,1H),8.90-8.70(m,2H),8.68-8.54(m,1H),8.20-8.05(m,2H),7.98(d,J＝9.0Hz,1H),7.67(t,J＝7.4Hz,1H),7.59(d,J＝3.6Hz,1H),3.61-3.37(m,2H),2.92(d,J＝4.4Hz,1H),2.18(s,1H),2.05(d,J＝11.6Hz,1H),1.95-1.72(m,4H),1.72-1.54(m,2H),1.38(d,J＝6.4Hz,3H),1.15(d,J＝11.6Hz,1H),0.75-0.63(m,4H)。[M+1]⁺458。

example 22b can also be synthesized using other procedures:

example 22 b: n-cyclopropyl-2- ((R) -1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H- Imidazo [4, 5-c)]Pyridine-6-carboxamides

Step 1: methyl 5-amino-4- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) Pyridine carboxylic acid ester

To a mixture of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionic acid (6.0g, 20mmol) and DMF (1 drop) in DCM (100mL) was added oxalyl chloride (6.0mL) dropwise, stirred at room temperature for 1 hour, and the reaction solution was concentrated to give (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride. To a solution of methyl 4, 5-diaminopicolinate (4.6g, 27.5mmol) and DIPEA (7.7g, 60mmol) in NMP (90mL) at 0 deg.C was added dropwise a solution of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride in DCM (65mL), the reaction mixture was stirred at room temperature for 16 hours, EA was added and washed with water and brine, Na2SO₄Dried, concentrated and purified by silica gel to give 6.1g of methyl 5-amino-4- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) Propionamido) picolinate.

Step 2: methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-c]6-Pyridinecarboxylic acid ester

At 0 ℃ to POPh₃(19g, 68mmol) in DCM (150mL) was added Tf dropwise₂A solution of O (9.5g, 33mmol) in DCM (30mL) was stirred for 15min, then methyl 5-amino-4- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) picolinate (6.7g, 14.9mmol) in DCM (50mL) was added and the reaction mixture was stirred at room temperature for 16 h and then warmed at room temperature for 16 h. The reaction mixture was washed with saturated NaHCO₃The aqueous solution was quenched, the DCM layer was concentrated and purified on silica gel to give 5.6g of methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-c]Pyridine-6-carboxylic acid ester.

And step 3: 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5- c]Pyridine-6-carboxylic acid

Methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-c]Pyridine-6-carboxylate (5.6g, 12.9mmol) and LiOH. H₂A solution of O (3.0g, 71.4mmol) was stirred at room temperature for 16H, the reaction mixture was concentrated, the pH of the residue was adjusted to 7 with 1N aqueous HCl, a white solid was collected and dried in vacuo to give 4.1g of 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-c]Pyridine-6-carboxylic acid.

And 4, step 4: n-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazole Azolo [4,5-c]Pyridine-6-carboxamides

2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4, 5-c)]A solution of pyridine-6-carboxylic acid (4.3g, 10.3mmol), cyclopropylamine (1.2g, 21mmol), HATU (4.5g, 11.8mmol) and DIPEA (6mL, 35mmol) in DMF (50mL) was stirred at room temperature for 16H, the reaction mixture was poured into water (450mL), a white solid was collected and purified by silica gel, then recrystallized from MTBE/acetonitrile/N-hexane (40mL/40mL/40mL) to give 1.7g pure N-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-c ] o]Pyridine-6-carboxamide.¹H NMR(400MHz,DMSO)δ_H 12.96(s,1H),8.90-8.70(m,2H),8.68-8.54(m,1H),8.20-8.05(m,2H),7.98(d,J＝9.0Hz,1H),7.67(t,J＝7.4Hz,1H),7.59(d,J＝3.6Hz,1H),3.61-3.37(m,2H),2.92(d,J＝4.4Hz,1H),2.18(s,1H),2.05(d,J＝11.6Hz,1H),1.95-1.72(m,4H),1.72-1.54(m,2H),1.38(d,J＝6.4Hz,3H),1.15(d,J＝11.6Hz,1H),0.75-0.63(m,4H)。[M+1]⁺458。

Example 23: 2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methyl-1H-imidazo [4,5-c]Pyridine-6-carboxamides

¹H NMR(400MHz,dmso)δ12.96(s,1H),8.95-8.78(m,2H),8.71(s,1H),8.22-8.04(m,2H),7.99(dd,J＝11.2,2.8Hz,1H),7.72-7.55(m,2H),3.51(dd,J＝10.8,6.8Hz,1H),3.43(s,1H),2.84(d,J＝4.8Hz,3H),2.17(d,J＝10.4Hz,1H),2.06(d,J＝12.4Hz,1H),1.97-1.72(m,4H),1.72-1.53(m,2H),1.38(d,J＝6.8Hz,3H)。[M+1]⁺432。

Examples 23a and 23b：2- ((S) -1- ((1S,4R) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -N-methyl- 1H-imidazo [4,5-c ]]Pyridine compound-6-carboxamidesAnd2- ((R) -1- ((1S,4S) -4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethane Yl) -N-methyl-1H-imidazo [4,5-c]Pyridine-6-carboxamides

Preparative HPLC was used at CHIRALPAK IC (Hex (8mM NH)₃MeOH): EtOH 60:40 as eluent) to separate each enantiomer of racemic compounds 23a and 23 b. The first enantiomer 23a (10.64mg) eluted at a retention time of 2.532min,¹H NMR(400MHz,dmso)δ12.96(s,1H),8.95-8.78(m,2H),8.71(s,1H),8.22-8.04(m,2H),7.99(dd,J＝11.2,2.8Hz,1H),7.72-7.55(m,2H),3.51(dd,J＝10.8,6.8Hz,1H),3.43(s,1H),2.84(d,J＝4.8Hz,3H),2.17(d,J＝10.4Hz,1H),2.06(d,J＝12.4Hz,1H),1.97-1.72(m,4H),1.72-1.53(m,2H),1.38(d,J＝6.8Hz,3H)。[M+1]⁺432. and the other enantiomer 23b (12.13mg) eluted at a retention time of 5.021min,¹H NMR(400MHz,dmso)δ12.96(s,1H),8.95-8.78(m,2H),8.71(s,1H),8.22-8.04(m,2H),7.99(dd,J＝11.2,2.8Hz,1H),7.72-7.55(m,2H),3.51(dd,J＝10.8,6.8Hz,1H),3.43(s,1H),2.84(d,J＝4.8Hz,3H),2.17(d,J＝10.4Hz,1H),2.06(d,J＝12.4Hz,1H),1.97-1.72(m,4H),1.72-1.53(m,2H),1.38(d,J＝6.8Hz,3H)。[M+1]⁺432。

example 24: n-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazole Azolo [4,5-b ] s]Pyridine-6-carboxamides

Step 1: methyl 6-amino-5- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) Nicotinic acid esters

To a solution of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionic acid (400mg, 1.33mmol) in DCM (10mL) was added DMF (1 drop) and oxalyl chloride (200mg, 1.55mmol) dropwise, and the mixture was stirred at room temperature for 2 hours and concentrated to give (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride. To methyl 5, 6-diaminonicotinate (700mg, 4.2mmol) and Et at 0 deg.C₃To a solution of N (700mg, 7.0mmol) in THF (20mL) was added dropwise a solution of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionyl chloride in THF (5mL), the reaction mixture was stirred at 0 deg.C for 30min, concentrated, EA added, washed with water and brine, Na₂SO₄Dried, concentrated and purified by silica gel to give methyl 6-amino-5- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) -nicotinate.

Step 2: methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-b]6-Pyridinecarboxylic acid ester

At 0 ℃ to POPh₃(560mg, 2.0mmol) in DCM (20mL) was added Tf dropwise₂A solution of O (280mg, 1.0mmol) in DCM (5mL) was stirred for 15min, then methyl 6-amino-5- ((R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamido) nicotinate (400mg, 0.89mmol) in DCM (5mL) was added and the reaction mixture was stirred at 0 ℃ for 30min and then warmed at room temperature for 16 h. The reaction mixture was washed with saturated NaHCO₃The aqueous solution was quenched, the DCM layer was concentrated and purified by silica gel to give methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-b]Pyridine-6-carboxylic acid ester.

And step 3: 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5- b]Pyridine-6-carboxylic acid

Methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-b]Pyridine-6-carboxylate (160mg, 0.37mmol) and LiOH. H₂A solution of O (40mg, 1.0mmol) was stirred at room temperature for 48H, the reaction mixture was concentrated, the pH of the residue was adjusted to 5 with 1N aqueous HCl solution, a white solid was collected and dried in vacuo to give 120mg of 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-b]Pyridine-6-carboxylic acid.

And 4, step 4: n-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazole Azolo [4,5-b ] s]Pyridine-6-carboxamides

2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-b]A solution of pyridine-6-carboxylic acid (120mg, 0.29mmol), cyclopropylamine (40mg, 0.7mmol), HATU (140mg, 0.37mmol) and DIPEA (150mg, 1.16mmol) in DMF (8mL) was stirred at room temperature for 16 h, EA was added, the mixture was washed with water and brine, over Na₂SO₄Dried, concentrated and purified by silica gel to give N-cyclopropyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4,5-b]Pyridine-6-carboxamide.¹H NMR(400MHz,DMSO-d)δ_H13.0(m,1H),8.87(d,J＝4.4Hz,1H),8.73(s,1H),8.51(s,1H),8.27(s,1H),8.10(dd,J＝9.2,5.6Hz,1H),7.98(dd,J＝6.8,2.4Hz,1H),7.66(dt,J＝8.8,2.4Hz,1H),7.58(d,J＝4.4Hz,1H),3.43(m,2H),2.87(m,1H),1.55-2.19(m,9H),1.37(d,J＝6.8Hz,3H),1.13-1.26(m,2H),0.71(m,2H),0.59(m,2H)。

Example 25:2- (1- ((1s,4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3, 7-dihydro-8H-imidazo [4,5-g]Quinazolin-8-ones

To a solution of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoic acid (301mg, 1.0mmol) in PPA (5mL) was added 6, 7-diaminoquinazolin-4 (3H) -one (200mg, 1.15 mmol). The mixture was stirred at 120 ℃ for 18 hours. The reaction mixture was poured into water (50ml) and sonicated for 5min, filtered, and washed with water (5ml × 2). The crude solid was purified by silica gel column chromatography (DCM/MeOH-100/0 to 90/10) to give the title compound.¹H NMR(400MHz,DMSO-d6)δ_H 12.68(m,1H),11.95(s,1H),8.87(d,J＝4.4Hz,1H),8.15-8.26(m,1H),8.10(dd,J＝9.2,6.0Hz,1H),7.98(m,2H),7.60-7.79(m,2H),7.60(d,J＝4.4Hz,1H),3.47(m,2H),2.19(m,1H),2.06(m,1H),1.86(m,3H),1.78(m,1H),1.67(m,1H),1.58(m,1H),1.38(m,3H),1.19(m,1H)。[M+H]+＝442.1。

Example 26: N-Ethyl-2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazole And [4,5-c ]]Pyridine-6-carboxamides

2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) -3H-imidazo [4, 5-c)]Pyridine-6-carboxylic acid (400mg, 0.96mmol), ethylamine hydrochloride (200mg, 2.44mmol), HATU (600mg, 1.58mmol) and Et₃A solution of N (700mg, 7.0mmol) in DMF (10mL) was stirred at room temperature for 16 h, EA was added, and the solution was washed with water and brine, over Na₂SO₄Dried, concentrated, and purified by silica gel to give 145mg of the title product.¹H NMR(400MHz,DMSO-d)δ_H 12.95(s,1H),8.87-8.66(m,3H),8.20-8.05(m,2H),7.98(dd,J＝11.0,2.6Hz,1H),7.70-7.63(m,1H),7.59(d,J＝4.3Hz,1H),3.47(m,2H),2.18(m,1H),2.04(m,1H),1.95-1.53(m,6H),1.38(d,J＝6.7Hz,3H),1.14(t,J＝7.1Hz,4H)。

Examples 27a and 27b (comparative example 1):4- ((1R,4S) -4- ((S) -1- (5, 6-difluoro-1H-benzo [ d)]Imidazole- 2-yl) ethyl) Cyclohexyl) -6-fluoroquinoline and 4- ((1S,4S) -4- ((R) -1- (5, 6-difluoro-1H-benzo [ d)]Imidazole-2- Yl) ethyl) cyclohexyl) -6-fluoroquinoline

Step 1: 4- ((1s,4s) -4- (1- (5, 6-difluoro-1H-benzo [ d)]Imidazol-2-yl) ethyl) cyclohexyl) -6-fluoro Quinolines

To a solution of (R) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoic acid (0.2g, 0.66mmol) in DMF (10mL) at room temperature were added HATU (0.3g, 0.8mmol), DIEA (0.5 mL). 4, 5-difluorobenzene-1, 2-diamine (0.14g, 0.8mmol) was then added. The mixture was stirred at 20-30 ℃ for 48 hours. The reaction mixture is then washed with H₂O (50mL) was quenched and extracted with EA (50 mL). The organic layer was separated and washed with brine (100mL) and concentrated to give the crude product(R) -N- (2-amino-4, 5-difluorophenyl) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamideIt was used in the next step without further purification.

A solution of (R) -N- (2-amino-4, 5-difluorophenyl) -2- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propionamide in HOAc (20mL) was stirred at 100 ℃ for 18 hours. The solvent was evaporated. The crude residue was dissolved with EA (50mL) and saturated NaHCO₃The solution (50mL) was washed. The organic phase was separated and purified by preparative HPLC to give4-((1s, 4s) -4- (1- (5, 6-difluoro-1H-benzo [ d ]]Imidazol-2-yl) ethyl) cyclohexyl) -6-fluoroquinoline。¹H NMR(400MHz,DMSO-d)δ_H 12.45(s,1H),8.86(d,J＝4.4Hz,1H),8.09(dd,J＝9.2,6.0Hz,1H),7.98(dd,J＝10.8,2.4Hz,1H),7.71-7.62(m,1H),7.58-7.40(m,3H),3.45-3.38(m,2H),2.16-1.99(m,2H),1.94-1.46(m,7H),1.33(d,J＝6.8Hz,3H)。[M+H]⁺＝409.9。

Step 2: 4- ((1R,4S) -4- ((S) -1- (5, 6)-difluoro-1H-benzo [ d]Imidazol-2-yl) ethyl) cyclohexyl) - 6-fluoroquinoline and 4- ((1S,4S) -4- ((R) -1- (5, 6-difluoro-1H-benzo [ d)]Imidazol-2-yl) ethyl) cyclohexyl) -6-fluoro Quinolines

Each enantiomer of racemates 27a and 27b was separated using preparative HPLC on CHIRALPAK IC (Hex: EtOH ═ 90:10 as eluent). The first enantiomer eluted at a retention time of 2.001min and the other enantiomer eluted at a retention time of 2.328 min. The eluate of 27a was concentrated to give the desired product as a white solid (4.20 mg).¹H NMR(MeOH-d6)δ_H 8.78(d,J＝4.8Hz,1H),8.07(dd,J＝9.2,5.6Hz,1H),7.86(dd,J＝10.4,2.8Hz,1H),7.68-7.48(m,2H),7.37(br,2H),3.47-3.41(m,2H),2.27-2.14(m,2H),2.06-1.63(m,7H),1.42(d,J＝6.4Hz,3H)。[M+H]⁺409.9. The eluate of 27b was concentrated to give the desired product as a white solid (60.3 mg).¹H NMR(MeOH-d6)δ_H 8.69(d,J＝4.8Hz,1H),7.98(dd,J＝9.2,5.6Hz,1H),7.77(dd,J＝10.8,2.4Hz,1H),7.61-7.45(m,2H),7.27(br,2H),3.38-3.33(m,2H),2.08(br,2H),1.99-1.52(m,7H),1.33(d,J＝6.8Hz,3H)。[M+H]⁺＝409.9。

Examples 28a to 29 were synthesized using procedures similar to examples 27a and 27 b.

Examples 28a and 28b (comparative example 2): methyl 2- ((S) -1- ((1S,4R) -4- (6-fluoroquinolin-4-yl) cyclohexan-e Yl) ethyl) -1H-benzo [ d]Imidazole-5-carboxylate and methyl 2- ((R) -1- ((1S,4S) -4- (6-fluoroquinolin-4-yl) cyclohexane Yl) ethyl) -1H-benzo [ d]5-Carboxylic acid imidazole ester

Separation of rac 28 using preparative HPLC on CHIRALPAK IC (Hex: EtOH ═ 70:30 as eluent)Each enantiomer of a and 28 b. The first enantiomer 28a (7.65mg) eluted at a retention time of 1.534 min.¹H NMR(MeOH-d6)δH 8.68(d,J＝4.8Hz,1H),8.13(s,1H),7.97(dd,J＝9.2,5.6Hz,1H),7.83-7.75(m,2H),7.53-7.42(m,3H),3.82(s,3H),3.45-3.31(m,2H),2.15-2.07(m,2H),1.95-1.54(m,7H),1.36(d,J＝6.8Hz,3H).[M+H]And 431.8. And the other enantiomer 28b (37.58mg) eluted at a retention time of 2.048 min.¹H NMR(MeOH-d6)δH8.77(d,J＝4.4Hz,1H),8.26-8.05(m,2H),7.94-7.81(m,2H),7.61-7.55(m,3H),3.91(s,3H),3.55-3.37(m,2H),2.28-2.13(m,2H),2.01-1.68(m,7H),1.45(d,J＝6.8Hz,3H).[M+H]+＝431.8。

Example 29 (comparative example 2): 6-fluoro-4- ((1S,4S) -4- ((R) -1- (4,5, 6-trifluoro-1H-benzo [ d)]Tooth-stick Oxazol-2-yl) ethyl) cyclohexyl) quinoline

¹H NMR(MeOH-d6)δ_H 12.78-13.07(m,1H),8.87(d,J＝4.0Hz,1H),8.10-7.97(m,2H),7.68-7.40(m,3H),3.43-3.42(m,2H),2.15-2.02(m,2H),1.89-1.56(m,6H),1.35(d,J＝6.4Hz,3H),1.17-1.14(m,1H)。

Example F: biological assay

IDO1 Kyn (kynurenine) production assay based on HeLa cells:

the inhibitory activity of IDO1 inhibitors was determined by measuring Kyn produced by oxidation of L-Trp (L-tryptophan) by cellular IDO1 in HeLa cells following IFN- γ -induced expression of IDO1 using a colorimetric reaction. Hela cells were obtained from the american type culture collection and were thawed in phenol red-free DMEM medium containing 10% FBS. Cells were seeded at 8000 cells per well in 96-well plates (100. mu.l/well) and provided with 5% CO₂Was maintained at 37 ℃ in a humidified incubator. After 4 hours, human recombinant IFN- γ (8901SC, CST) was added to the cells (final concentration of 100ng/mL) to stimulate endogenous IDO 1. IFN-. gamma.and 0.4mM L-Trp were added simultaneously to different concentrations of compounds diluted in dimethyl sulfoxide (DMSO).Cells were supplied with 5% CO₂Was maintained at 37 ℃ in a humidified incubator. After 48 hours of incubation, 100 μ l of supernatant from each well was transferred to a new plate. The protein in the medium was precipitated by addition of 8. mu.l of 6N trichloroacetic acid. The plates were incubated at 60 ℃ for 30 minutes and then centrifuged at 2500rpm for 10 minutes to remove the precipitate. 80 μ l of the supernatant was carefully transferred to a new clean plate and an equal volume of 2% 4- (dimethylamino) benzaldehyde (D2004, Sigma) dissolved in glacial acetic acid was added. The absorbance derived from Kyn at a wavelength of 480nm was measured using a PHERAStar FS plate reader (BMG LABTECH Co.). The IC of each compound was derived by fitting dose-response data to a four-parameter logistic model using XLFit software (IDBS)₅₀。

Plasma protein binding assay:

to assess the extent of binding of plasma proteins, the bound (fb) and unbound (fu) fractions of test compounds will be determined in vitro by equilibrium Dialysis methods using a 96-well Dialysis unit (HT Dialysis, Gales Ferry, connecticut, usa). Equilibrium dialysis will be performed in duplicate. 150 μ L of 50% plasma incorporating test compounds (final concentration of 5 μ M) was added to the donor side and 150 μ L of Phosphate Buffer (PB) (0.002% Tween-80) was added to the respective receiver sides. The device was then sealed with a glue film and shaken at 80rpm in a water bath at 37 ℃ for 6 h. At the end of incubation, 10 μ L of plasma sample was transferred from the donor side to a 1.5mL microcentrifuge tube, 90 μ L PB (0.002% tween-80) was added, vortexed uniformly, and proteins were precipitated with acetonitrile containing Internal Standard (IS). A90 μ L sample of PB (0.002% Tween-80) was transferred from the receiving side to a 1.5mL microcentrifuge tube, 10 μ L of 50% blank plasma was added, vortexed uniformly, and the protein was precipitated with IS-containing acetonitrile.

For recovery checks, 10 μ Ι of donor-side loaded sample was aliquoted into 1.5mL microcentrifuge tubes (in duplicate), 90 μ Ι _ PB (0.002% tween-80) was added, vortexed uniformly, and proteins were precipitated with IS-containing acetonitrile.

For plasma stability checks, 10 μ Ι of donor-side loaded sample was aliquoted into 1.5mL microcentrifuge tubes (in duplicate), incubated in a water bath at 37 ℃ for 6h, at the end of the incubation 90 μ Ι _ of PB (0.002% tween-80) solution was added, vortexed uniformly, and proteins were precipitated with IS-containing acetonitrile.

Biological analysis

Appropriate LC-MS/MS methods will be developed for analysis of test compounds or control compounds in the incubations.

Data analysis

The unbound fraction (fu) of test compound and positive control compound in 50% plasma will be calculated using the following equation.

Wherein C is_RIS the area ratio of test compound to IS in the receiving side, C_DIS the area ratio of test compound to IS in the respective donor side, and D IS the plasma dilution factor.

₅₀Table 1: 1H-benzo [ d ]]Cellular Activity data EC for imidazole (binding of IDO1 to plasma proteins based on Hela cells)

The data in this table shows that the non-amide substituted imidazo compounds have a higher PPB than the amide substituted compounds.

Representative compounds disclosed herein were shown to inhibit Hela cell-based IDO1, with EC₅₀Values ranged from less than 10000 nM.

It is to be understood that if any prior art publication is referred to herein; such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

In the claims which follow and in the preceding embodiments of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

The disclosures of all publications, patents, patent applications, and published patent applications cited herein are hereby incorporated by reference in their entirety.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those of ordinary skill in the art that certain minor modifications and adaptations can be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

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